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Role of inflammasomes in cancer immunity: mechanisms and therapeutic potential

Journal of Experimental & Clinical Cancer Research volume 44, Article number: 109 (2025) Cite this article

Abstract

Inflammasomes are multi-protein complexes that detect pathogenic and damage-associated molecular patterns, activating caspase-1, pyroptosis, and the maturation of pro-inflammatory cytokines such as IL-1β and IL-18Within the tumor microenvironment, inflammasomes like NLRP3 play critical roles in cancer initiation, promotion, and progression. Their activation influences the crosstalk between innate and adaptive immunity by modulating immune cell recruitment, cytokine secretion, and T-cell differentiation. While inflammasomes can contribute to tumor growth and metastasis through chronic inflammation, their components also present novel therapeutic targets. Several inhibitors targeting inflammasome components- such as sensor proteins (e.g., NLRP3, AIM2), adaptor proteins (e.g., ASC), caspase-1, and downstream cytokines- are being explored to modulate inflammasome activity. These therapeutic strategies aim to modulate inflammasome activity to enhance anti-tumor immune responses and improve clinical outcomes. Understanding the role of inflammasomes in cancer immunity is crucial for developing interventions that effectively bridge innate and adaptive immune responses for better therapeutic outcomes.

Background

Inflammasomes, large multi-protein complexes that form in response to endogenous danger signals within the cytosol, are key players in triggering inflammatory immune responses. Their formation activates caspase-1, a critical inflammatory protease, leading to pyroptosis and the conversion of pro-inflammatory cytokines, such as pro-IL-1β and pro-IL-18, into their active forms [1]. The complex comprises a Nod-like receptor (NLR), the adaptor protein ASC, and caspase-1. While the NLRP3 inflammasome plays a crucial role in tumor pathogenesis, its role in cancer development and progression remains controversial due to conflicting findings [2]. The inflammatory tumor microenvironment is intricately involved in all stages of cancer, from initiation to promotion and progression. Systemic inflammation in this environment has become a significant prognostic indicator in cancer patients [3, 4]. Inflammasomes play a central role in this process by detecting pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), which signal the recruitment of immune cells to sites of infection or injury [5, 6], dysregulation of inflammasome expression or activation linked to various inflammatory disorders. Recent evidence highlights the role of inflammasomes in cancer development and progression, with particular emphasis on the downstream effector cytokine IL-1β [7, 8]. Emerging research has shown that inflammasome activation can be triggered by oncogenic stress and metabolic disturbances, although its full role in cancer biology remains unclear. NLRP3 has emerged as a critical factor influencing tumor progression, functioning through both pro- and anti-tumorigenic pathways [9, 10]. Understanding these mechanisms is crucial as it can potentially modulate inflammasomes for therapeutic purposes, including tumor growth inhibition and metastasis control. This review aims to inform the audience about the intricate role of NLRP3 in cancer by summarizing findings across various tissue contexts and cancer hallmarks, focusing on evaluating its potential as a therapeutic target.

Inflammasomes have emerged as potential targets for disease-modifying therapies, with several clinical trials underway to investigate their therapeutic potential (Fig. 1). These ongoing trials could lead to new therapeutic regimens for various inflammatory disorders and cancers [11,12,13]. The innate immune pathway has gained traction in cancer therapy due to its role in different cell types, including immune, tumor, and stromal cells. Preclinical studies have shown that targeting this pathway with specific agonists can remodel the tumor microenvironment and improve the prognosis [14]. However, clinical success is still limited, as activation of this pathway can also promote tumor progression, depending on factors such as tumor stage, pathway status, and the specific organ or tissue involved. A deeper understanding of the innate immune pathway within the tumor microenvironment could enhance its anti-tumor potential and improve clinical outcomes [15]. Moreover, inflammasomes, as key players in regulating innate and adaptive immunity, provide a fascinating bridge between these two arms of the immune system. This review explores how inflammasomes link these two arms, mainly focusing on their role in immune responses and their interaction with metabolic signals. These insights provide valuable opportunities for identifying new therapeutic targets [16]. While adaptive immunity helps to control or prevent cancer growth, innate immunity, and inflammation often contribute to tumor initiation and progression. Despite significant progress in developing cancer immunotherapies, targeting cancer-related inflammation remains challenging. Anti-inflammatory therapies promise to prevent or delay cancer onset and enhance traditional treatments and immunotherapies [17]. This review highlights recent research and clinical developments that support anti-inflammatory strategies in treating solid tumors, emphasizing the importance of understanding the underlying mechanisms for designing more effective treatment combinations [18].

Fig. 1
figure 1

An overview of key milestones in inflammasome research and their applications. Blue boxes indicate discoveries of key components of different inflammasomes; the pink box marks the origin of the term "inflammasome"; green boxes show associations between inflammasomes and various human diseases; and purple boxes represent representative clinical applications of inflammasome-related modulators

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Inflammasome

The term "inflammasome" was coined by Tschopp and colleagues in 2002 to describe a protein complex responsible for activating inflammatory caspases [19]. This collaborative effort has significantly advanced our understanding of the immune system. Inflammasomes are large molecular complexes that become activated in response to various pathogen infections or cellular stresses, rapidly producing pro-inflammatory cytokines. These cytokines play a critical role in recruiting innate immune cells to fight off invading pathogens [20, 21]. Dysregulation of inflammasome activity has been associated with tumor development [22]. Inflammasomes are broadly categorized into "classical" and "non-classical" inflammasomes based on the specific caspase enzymes they activate [23]. Classical inflammasomes comprise several proteins, including pattern recognition receptors (PRRs), the adaptor protein ASC, and pro-cysteine-requiring aspartate protease-1 (pro-caspase-1). Interestingly, some PRRs are also expressed in adaptive immune cells, which regulate antigen presentation [24]. PRRs involved in innate immunity are classified into two main types: transmembrane proteins, such as Toll-like receptors (TLRs) and C-type lectin receptors (CLRs), and cytoplasmic proteins, including RIG-I-like receptors (RLRs) and Nod-like receptors (NLRs) [25]. The discovery of the first inflammasome-related PRR in 2002 led to the identification of multiple inflammasomes, including NLRP1, NLRP2, NLRP3, absent in melanoma 2 (AIM2), and NLRC4 [26, 27], as shown in Fig. 2. Among these, the NLRP3 inflammasome, also known as pyrin domain-containing protein 3, has been extensively studied for its role in inflammation [28]. NLRs are cytoplasmic PRRs, and their activation requires two signals for optimal function. The first signal, or priming, is initiated by external stimuli like tumor necrosis factor (TNF), IL-1β, or pathogen-associated molecular patterns (PAMPs), which enhance the expression of inflammasome components and pro-inflammatory cytokines. The second signal, typically provided by PAMPs or damage-associated molecular patterns (DAMPs), results in the oligomerization and assembly of inflammasome components [29]. The formation of inflammasomes involves oligomerizing receptor proteins such as NLRP1, NLRP3, NLRC4, AIM2, and pyrin. PAMPs are recognized by PRRs, which are essential for detecting pathogenic threats or cellular damage. DAMPs, including extracellular ATP, ion flux changes, lysosomal damage, mitochondrial reactive oxygen species (mtROS), and oxidized mitochondrial DNA (ox-mtDNA), also activate the NLRP3 inflammasome [30, 31]. Upon PRR activation, classical inflammasomes bind to ASC via domains such as the caspase recruitment domain (CARD) or pyrin domain (PYD), forming oligomeric structures that recruit and activate pro-caspase-1. Activated caspase-1 cleaves pro-interleukin-1β (pro-IL-1β) and pro-interleukin-18 (pro-IL-18) into their mature, active forms. These cytokines facilitate immune responses by recruiting inflammatory and immune cells to the site of infection, thereby contributing to innate immunity [10]. Active IL-1β functions as a potent pro-inflammatory cytokine, attracting immune cells to the affected site, while active IL-18 promotes interferon-γ (IFN-γ) production, which enhances the activity of natural killer (NK) cells and T cells [20, 32]. Caspase-1 also cleaves Gasdermin D (GSDMD), causing pore formation and lysis of the cell membrane, which leads to a distinct form of inflammatory cell death known as pyroptosis [33]. In contrast, non-classical inflammasomes primarily activate caspases such as Caspase-3, 4, 5, 7, 8, and 11 rather than caspase-1 [23], as illustrated in Fig. 3.

Fig. 2
figure 2

Representative structures of inflammasome sensor proteins and their complex assemblies. A This figure illustrates the representative structures of inflammasome sensor proteins, including NLRPs (such as NLRP1 and NLRP3), NLRCs (such as NLRC4), and ALRs (such as AIM2). B It also highlights the representative structures of various inflammasomes, such as the NLRP1, NLRP3, NLRC4, and AIM2 inflammasomes. Key terms include: NLRs (Nucleotide-binding domain, leucine-rich repeat-containing proteins), NLRPs (A subset of NLRs with an N-terminal pyrin domain (PYD)), NLRCs (NLRs with a caspase activation and recruitment domain (CARD)), ALRs (AIM2-like receptors, such as absent in melanoma 2), NAIP (NLR apoptosis inhibitory protein)

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Fig. 3
figure 3

Mechanism of Activation and Signaling Pathways of the NLRP3 Inflammasome. This figure illustrates the activation and signaling mechanisms of the NLRP3 inflammasome, featuring key components such as Bruton's tyrosine kinase (BTK), calcium/calmodulin-dependent protein kinase II (CaMKII), and protein kinase R (PKR). It highlights how damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) interact with nucleotide-binding oligomerization domain (NOD)-like receptors like NLRP3 (NOD-like receptor family pyrin domain-containing 3). Other important elements include DEAH-box helicase 33 (DHX33), the endoplasmic reticulum (ER), interleukins (IL), Janus kinase 1 (JAK1), lipopolysaccharide (LPS), the mitochondrial calcium uniporter (MCU), nuclear factor kappa B (NF-κB), the small heterodimer partner (SHP), tumor necrosis factor (TNF), tripartite motif-containing protein 33 (TRIM33), and voltage-dependent anion channels 1 and 2 (VDAC1/2)

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The role of inflammasomes in health and disease

Dysregulated inflammasome activity has been associated with the onset and progression of a wide range of diseases, including diabetes, cancer, and various cardiovascular and neurodegenerative disorders. Consequently, recent studies have increasingly focused on elucidating the mechanisms underlying inflammasome assembly and activation and exploring their potential as therapeutic [34,35,36]. Importantly, several clinical trials are currently underway to assess the efficacy of different therapies that modulate inflammasome activity, providing a real-time update on the state of research. Understanding the contributions of various inflammasomes to disease pathogenesis could significantly impact the development of novel therapeutic strategies [37, 38]. Notably, Inflammation is closely linked with the hallmarks of cancer. NLRP3 plays a dual role in cancer, contributing to tumor-promoting inflammation and immune evasion while influencing immune surveillance. In cervical and prostate cancers, NLRP3 is activated by pathogens and oncogenic stress [2, 38, 39]. In breast cancer, it enhances sphingosine-1-phosphate (S1P) signaling in tumor-associated macrophages (TAMs) and promotes metastasis by recruiting γ/δ T cells [40, 41]. In colorectal cancer (CRC), liver metastasis, fibrosarcoma, and lymphoma, NLRP3 inhibition suppresses tumor migration, while its activation promotes metastatic spread [42,43,44]. In pancreatic cancer, it enhances survival via NF-κB signaling and is regulated by PDL1 and CTLA4 [45, 46]. In skin and bone metastases, NLRP3 suppresses NK and T cell responses, favoring tumor progression [44, 47]. Conversely, in CRC liver metastases, HNSCC, and NPC, NLRP3 plays a significant role in promoting immune surveillance, boosting NK cytotoxicity, reshaping the anti-tumor response, and preventing local relapse through IL-1β-driven recruitment of anti-tumor neutrophils [48,49,50] (Table 1). Here, we aim to provide an overview of inflammasomes' biological and pathological roles that support their potential as promising targets for cancer therapy.

Table 1 Inflammation: A key driver of cancer hallmarks
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Role of innate and adaptive immunity in cancer

The innate immune system acts as the body's first line of defense, recognizing and eliminating pathogens while activating the adaptive immune system. It consists of physical barriers (such as skin and mucosa), effector cells (including phagocytes, epithelial and endothelial cells, natural killer cells, and innate lymphoid cells), secretions, and pattern recognition receptors (PRRs), including Toll-like receptors [51]. The presence of inflammatory cells within tumors raises a critical question in oncology: How do cancer cells evade immune destruction? Since identifying inflammatory cells in tumors, considerable effort has been devoted to understanding their complex roles in cancer. It is now well established that dysregulation of both innate and adaptive immune responses significantly contributes to tumorigenesis by fostering the selection of aggressive clones, inducing immunosuppression, and promoting cancer cell proliferation and metastasis [52, 53].

Inflammation is a biological response mounted by the body to infections, wounds, and chemical exposure to restore homeostasis and preserve tissue function [54]. The cells and molecules responsible for initiating and coordinating inflammation are critical components of the innate immune system. Tissue-resident macrophages and mast cells are the first responders to harmful stimuli, secreting mediators, including cytokines and chemokines, to recruit other innate immune cells to sites of infection or injury. Neutrophils are among the first cells to respond to these signals, activating and eliminating invading bacteria [55]. If the acute inflammatory response is insufficient to eradicate the insult, macrophages, and T cells are recruited and activated by increased levels of chemokines, growth factors, and cytokines. This process is followed by a resolution phase, during which the local release of signals such as resolvins, protectins, and transforming growth factor β (TGF-β) inhibits further neutrophil recruitment [56]. Instead, monocytes are recruited to the site, differentiate into macrophages, clear dead cells, and initiate tissue repair mechanisms. Chronic inflammation may ensue if the acute inflammatory response fails to resolve correctly [57]. In 1986, Harold F. Dvorak drew a parallel between tumors and "wounds that do not heal," suggesting that tumors can trigger an inflammatory wound-healing response, thus creating favorable conditions for survival and growth [58].

Local inflammation can drive cancer development and progression within the same tissue or organ [59]. For instance, several infections can promote cancer:

  1. 1.

    Helicobacter pylori-induced gastritis can progress to gastric cancer.

  2. 2.

    Chronic hepatitis B or C virus infections can lead to liver cancer.

  3. 3.

    Unresolved infection with human papillomavirus (HPV) can result in cervical cancer.

In addition to the direct carcinogenic effects of these pathogens, the persistent inflammatory environment resulting from failure to clear the infection contributes to cancer development [60, 61]. Chronic inflammatory diseases, even without infections, can also establish a microenvironment primed for tumor development.

The innate immune system comprises various immune cells of myeloid and lymphoid origins and multiple classes of proteins, including cytokines, chemokines, receptors, and complement system components. The activity of these immune elements is not inherently tumor-supportive or tumor-suppressive; instead, their effects depend on the abundance and type of immune cells present in each tissue, the balance of signals within the tumor microenvironment (TME), and the stage of tumor progression. For example, while lung cancer cells engineered to express a potent antigen are rejected by cytotoxic T cells in the lung, similar antigen expression in pancreatic cancer cells can exacerbate the disease, as this site has fewer dendritic cells capable of activating T cells [62]. Additionally, innate immune cells are highly plastic, and their phenotype and function adapt to changes in the local microenvironment. Myeloid cells are heterogeneous, derived from a common progenitor in the bone marrow. They are recruited to tumors and regulate cancer progression, from initiation to invasion and metastasis. The central myeloid cells studied in cancer include macrophages/monocytes, neutrophils, myeloid-derived suppressor cells (MDSCs), and dendritic cells (DCs). Macrophages are large phagocytic cells essential for host defense, especially against bacterial infections, and for maintaining tissue homeostasis by clearing cellular debris and dysfunctional cells. Tissue-resident macrophages originate during embryogenesis, but bone marrow-derived monocytes can also differentiate into macrophages, mainly when recruited in response to injury or infection [63]. Macrophages and their monocyte precursors are often the most abundant immune cell type in solid tumors and are critical contributors to cancer-associated inflammation [64]. Activated inflammatory macrophages release reactive nitrogen species (RNS) and reactive oxygen species (ROS), which have mutagenic potential, as well as cytokines such as tumor necrosis factor α (TNF-α) and interleukins (e.g., IL-1β, IL-6, and IL-12), providing a conducive environment for the development of chronic inflammation-associated cancers. Neutrophils are some of the earliest immune cells to arrive at sites of tissue damage. They combat pathogens through phagocytosis, release of antibacterial proteins and proteases, and formation of neutrophil extracellular traps (NETs) [65]. Factors such as granulocyte-colony stimulating factor (G-CSF) and other cytokines that promote neutrophil differentiation and release from the bone marrow are often elevated in the tumor environment and systemically in cancer patients, resulting in an increased presence of both mature and immature neutrophils [66].

MDSCs are a heterogeneous population of immature myeloid cells that expand significantly during pathological conditions like cancer. MDSCs are typically categorized into two subgroups: monocytic MDSCs (M-MDSCs) and polymorphonuclear or granulocytic MDSCs (PMN-MDSCs). These cells resemble monocytes and neutrophils morphologically and phenotypically but are characterized by their ability to suppress T cell activity. MDSC expansion is driven by cytokines such as GM-CSF, G-CSF, M-CSF, IL-6, and VEGF, while their immunosuppressive function requires activation by IL-4, IL-13, or TGF-β [67]. DCs are critical players in the innate immune system and serve as a bridge to adaptive immunity. They constantly sample their environment for antigens, danger signals, and pathogens. Upon encountering antigens, DCs migrate to lymphoid tissues (such as the thymus, spleen, and lymph nodes), where they present these antigens to T and B cells through major histocompatibility complex (MHC) class I and II, stimulating antigen-specific immune responses [68]. DCs are traditionally divided into two central populations: conventional DCs (cDCs) and plasmacytoid DCs (pDCs) [69]. Adaptive immunity, mediated by T and B cells, is the body's targeted immune response to specific antigens and can generate long-term immune memory for prolonged protection. T cells differentiate into various subtypes, including CD4 + helper T cells (Th) and CD8 + cytotoxic T cells (CTLs), each with specialized functions. Proper regulation of T cell activation, differentiation, and effector functions is crucial to eliminate infections or tumor cells while avoiding excessive immune reactions or autoimmunity (Fig. 4).

Fig. 4
figure 4

Inflammasomes mediate the dynamic interplay between innate and adaptive immunity, shaping immune responses. A Inflammasomes in antigen-presenting cells (APCs) release IL-1 family cytokines and HMGB1, which have a significant impact on T cell immune responses. The arrows in the figure are color-coded to match the font color of the effects they represent. Activation of inflammasomes can also trigger the expression of specific genes in innate immune cells, thereby influencing adaptive immunity. For instance, in macrophages, the AIM2 inflammasome is activated upon recognition of phagocytosed tumor DNA following antibody-dependent cellular phagocytosis (ADCP). This activation leads to the upregulation of IDO and PD-L1, resulting in T cell immunosuppression. Additionally, a deficiency of Tim-3 in dendritic cells (DCs) causes an accumulation of reactive oxygen species (ROS) and subsequent activation of the NLRP3 inflammasome, which enhances the stemness and effector functions of CD8⁺ T cells. B Cytokines produced by T cells can modulate the activation or inhibition of inflammasomes in APCs. T cells that secrete perforin and TNF-α can activate the NLRP3 inflammasome, while cytokines like IL-10 and IFN-γ inhibit its assembly. Moreover, the activation of CD8⁺ T cells in response to anti-PD-1 therapy initiates a PD-L1/NLRP3 inflammasome signaling cascade. This cascade ultimately leads to the recruitment of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) into tumor tissues, providing negative feedback that inhibits CD8⁺ T cell activation and anti-tumor immune responses

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Fundamental roles of inflammasomes in innate immunity

The immune system is essential for eliminating pathogens, repairing tissue damage, and restoring homeostasis. Inflammasomes are critical components in these innate immune responses. The innate immune system uses germline-encoded pattern recognition receptors (PRRs) to identify microbial threats and damage-associated signals [17]. PRRs are expressed by various cell types, including macrophages, monocytes, dendritic cells, neutrophils, and epithelial cells, which form the first line of defense in the immune system. Acute inflammation is a normal physiological response to infection or tissue injury, and it must be adequately resolved to prevent the onset of chronic inflammation. Chronic unresolved inflammation has been linked to various disorders, including metabolic diseases, autoimmune conditions, and cancer [36]. Research indicates that coordinated resolution mechanisms are initiated shortly after an inflammatory response begins [70]. During this phase, inflammatory cells undergo functional reprogramming to shift from a pro-inflammatory state to a pro-resolving phase [37].

Interestingly, specific molecules involved in the acute inflammatory phase, such as IL-1β, also promote anti-inflammatory responses by inducing the production of IL-10. Inflammasomes play a central role in regulating the expression, maturation, and release of IL-1β, a key regulator of inflammation. At sites of infection or injury, IL-1β promotes the expression of genes involved in inflammation, such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), leading to the production of prostaglandin E2 and nitric oxide, respectively. Furthermore, IL-1β enhances the expression of adhesion molecules, including intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), which facilitate immune cell recruitment to the site of infection or injury. In addition to IL-1β, inflammasomes are also involved in the production of IL-18, another pro-inflammatory cytokine that plays a role in inducing IL-17 expression in Th17 cells and in shaping T cell differentiation towards Th1 or Th2 phenotypes, depending on the context and availability of other cytokines [10]. However, compared to IL-1β, the role of IL-18 in the tumor microenvironment is less defined. Inflammasomes are closely associated with macrophage polarization. Activation of the NLRP3 inflammasome leads to a pro-inflammatory macrophage phenotype characterized by the production of TNF, IL-6, and IL-1β [71, 72].

In contrast, inhibition of NLRP3 signaling promotes the differentiation of microglial cells into an anti-inflammatory phenotype [73]. Macrophages are also essential in cancer initiation and progression. Tumor-associated macrophages (TAMs) comprise a substantial portion of immune cells within the tumor microenvironment (TME), and their heterogeneity affects the efficacy of cancer immunotherapy [64].

Interestingly, a specific population of CD146 + macrophages within the TME has been found to enhance anti-tumor immunity through NLRP3 inflammasome activation [64]. In conventional human dendritic cells (cDCs), the cDC1 subset undergoes cell death following inflammasome activation, whereas the cDC2 subset remains hyperactivated. The cDC2 subset continues to bridge innate and adaptive immunity, particularly in response to inflammasome signals, including NLRP3 activation, which enhances overall immune activity [74, 75]. Neutrophils also play a role in inflammasome activation. During bacterial infections, neutrophils activate inflammasomes such as NLRP3, NLRC4, and NLRP12, becoming a significant source of caspase-1-dependent IL-1β production [76]. Unlike other immune cells, neutrophils do not undergo pyroptosis following canonical inflammasome activation, which might be due to the localization of the N-terminal fragment of gasdermin D (N-GSDMD) in azurophilic granules and LC3 autophagosomes rather than at the plasma membrane [77].

Recent findings suggest that early neutrophil activation involves rapid activation of the NLRP3 inflammasome, which E-selectin triggers. This process entails the transient translocation of GSDMD to the plasma membrane, followed by the release of S100A8/S100A9, and is promptly terminated by ESCRT-III-mediated membrane repair [78]. Additionally, neutrophils secrete IL-1β through distinct, gasdermin-independent mechanisms. Studies involving autophagy-related gene 7 (ATG7)-deficient cells have shown that autophagy is necessary for IL-1β secretion in neutrophils [79]. Furthermore, non-canonical inflammasome activation triggers neutrophil NETosis (gasdermin D-induced cell death) and the release of antimicrobial neutrophil extracellular traps (NETs) through caspase-4/5 in humans and caspase-11 in mice [80]. Recent research also indicates that NLRP3 inflammasome activation in neutrophils promotes NETosis under sterile conditions, such as during the progression of venous thrombosis [81], as shown in Fig. 4A. These findings underscore the significant role of neutrophils in inflammasome activation and highlight the need for further research in this area.

Inflammasomes role in adaptive immunity

Recent studies have demonstrated that T-cell inflammasome activation is critical in regulating immune responses. In B cells, the NLRP3 inflammasome promotes B cell expansion in adipose tissue, particularly during CpG stimulation. Inhibiting NLRP3-dependent B cell expansion has been shown to reverse metabolic disruptions in aging adipose tissue. Additionally, stimulation of B cells with CpG leads to the activation of NLRP3 and caspase-1, along with the production and secretion of IgM antibodies [82, 83]. In addition to their role in B cells, inflammasomes are also present in T cells, influencing cytokine production and differentiation. Given T-cells' crucial role in adaptive immunity, understanding the mechanisms behind inflammasome activation and regulation within these cells is essential. Initially, inflammasomes were thought to be exclusive to innate immune cells. However, emerging evidence suggests that adaptive immune cells, such as T and B cells, exhibit non-self-recognition behaviors mediated by specific pattern recognition receptor (PRR) systems [84, 85]. These PRRs enhance antigen-driven T-cell responses, trigger effector cytokine release, and activate bystander cells [86].

Effect of inflammasome activation on T cell function

Inflammasome activation in T cells primarily leads to the maturation and release of pro-inflammatory cytokines, such as IL-1β and IL-18. Once secreted, these cytokines significantly influence T cell activation, proliferation, differentiation, and effector responses through interactions with their receptors, IL-1R and IL-18R. These interactions complement antigen receptor and co-stimulatory signals to enhance the immune response [87]. For instance, in human CD4 + T cells, activation of the NLRP3 inflammasome triggers caspase-1-dependent secretion of IL-1β. This autocrine signaling stimulates the production of IFN-γ and promotes differentiation into Th1 cells, enhancing their pro-inflammatory role in immune responses [88,89,90]. Thus, inflammasome activation regulates cytokine secretion and primes T-cell differentiation and function, particularly during immune responses to pathogens or tumors.

Pyroptosis in the regulation of adaptive immunity by inflammasomes

Pyroptosis, a form of programmed cell death, can release large amounts of inflammatory cytokines and potential antigens. The most extensively studied aspect of pyroptosis is its activation through inflammasomes, which promotes the maturation and extracellular release of IL-1β and IL-18. These cytokines modulate adaptive immune functions, including T and B cell responses. This process has been discussed in detail previously. In addition to cytokine release, pyroptosis facilitates the release of small cytoplasmic proteins through gasdermin pores [91], eventually causing cell membrane rupture. This rupture releases large protein complexes such as tetrameric lactate dehydrogenase, lipid mediators, and high mobility group box 1 (HMGB1), a potent pro-inflammatory mediator. The release of these molecules can directly or indirectly influence the function and differentiation of T and B cells. For example, HMGB1 is released extracellularly when immune cells are activated or their membranes are damaged, acting as a pro-inflammatory mediator that promotes an immune response [92]. In LPS-primed macrophages, inflammasome activation triggers caspase activity, facilitating HMGB1 secretion [93]. After cell pyroptosis and membrane rupture, HMGB1 is further released into the extracellular space, contributing to inflammatory signaling [94]. This illustrates how pyroptosis contributes to innate immune responses and influences adaptive immunity by releasing molecules that modulate T and B cell functions.

Interplay of adaptive and innate immunity

While inflammasome activation in innate immune cells affects adaptive immunity, adaptive immune cells, such as T cells, can also modulate innate immune responses via inflammasome pathways. Specifically, antigen-specific cytotoxic T lymphocytes (CTLs) can activate the NLRP3 inflammasome in antigen-presenting cells (APCs), including dendritic cells and macrophages, through perforin. This results in IL-1β maturation in APCs, creating a positive feedback loop. The secretion of IL-1β by APCs further enhances the priming, activation, and proliferation of CD4 + T cells and CTLs [95]. In the context of immune checkpoint blockade (ICB) therapy, particularly with anti-PD-1 (programmed cell death protein 1) agents, CD8 + T cells that are unblocked by PD-1 inhibition initiate the PD-L1/NLRP3 inflammasome signaling cascade, which recruits granulocytic myeloid-derived suppressor cells (MDSCs) into the tumor microenvironment, thereby enhancing anti-tumor responses [96]. This dynamic interaction between adaptive and innate immunity highlights the bidirectional influence of inflammasome activation in coordinating immune responses, particularly in cancer immunotherapy and immune regulation. Effector and memory CD4 + T cells can suppress inflammasome-mediated caspase-1 activation and IL-1β release in macrophages by downregulating NLRP1 and NLRP3 inflammasomes. For example, in an NLRP3-dependent peritonitis model, effector CD4 + T cells reduce neutrophil recruitment in an antigen-specific manner [97,98,99]. Additionally, type 1 regulatory T (Tr1) cells, a subset of CD4 + regulatory T cells, inhibit NLRP3 inflammasome activation in macrophages through the secretion of IL-10. Mechanistically, IL-10 promotes mitochondrial autophagy and prevents the accumulation of reactive oxygen species (ROS), inhibiting NLRP3 inflammasome activation. IL-10 also downregulates pro-IL-1β mRNA transcription, caspase-1 activation, and mature IL-1β release in macrophages via the STAT3 signaling pathway [100,101,102,103]. Beyond CD4 + and CD8 + T cells, IL-2-stimulated invariant natural killer T (iNKT) cells activate human peripheral blood monocytes through a contact-dependent mechanism, possibly involving interactions with NF-κB signaling receptors in monocytes. This interaction promotes IL-1β transcription and NLRP3 inflammasome-dependent caspase-1 activation, producing IL-1β secretion from monocytes [21]. Furthermore, TNF-α secreted by NKT cells enhances NLRP3 inflammasome activation in APCs, such as dendritic cells, monocytes, and macrophages, leading to the secretion of IL-1β and IL-18 [104]. These findings indicate that adaptive immune cells can modulate innate immune responses through inflammasome activation. However, more research is needed to fully explain the regulatory mechanisms of inflammasomes that bridge innate and adaptive immunity and their role in immune-related diseases (Fig. 4B).

Inflammasome-targeted therapy

Due to their role in a variety of diseases, inflammasomes have emerged as promising targets for therapeutic intervention. Currently, most FDA-approved drugs act on pathways associated with inflammasome activity rather than directly inhibiting the inflammasomes themselves. However, ongoing research is focused on developing therapies that specifically target inflammasomes, as described in in Fig. 5 and Table 2.

Fig. 5
figure 5

Inhibitors of inflammasomes and related pathways. This figure highlights various inhibitors that specifically target key components of inflammasomes activation, including NLRP1, NLRP3, AIM2, ASC, caspase-1, interleukin-1β, interleukin-18, and GSDMD. These inhibitors by effectively blocking inflammasome activation, suppress pyroptosis and the release of pro-inflammatory cytokines, offering potential therapeutic strategies for inflammation-driven cancer and other diseases

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Table 2 Overview of current clinical trials targeting inflammation in cancer
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Sensor protein modulation

Considerable efforts have been made in recent years to develop inhibitors that target inflammasome sensor proteins as potential treatments for inflammatory diseases. For example, cytosolic DPP9 binds to the C-terminus of NLRP1, thereby preventing inflammasome activation [105, 106]. MCC950, an inhibitor of NLRP3, blocks activation by targeting its NACHT domain, explicitly inhibiting the Walker B motif and preventing ATP hydrolysis [107]. Tranilast, commonly used for allergies, disrupts NLRP3 inflammasome assembly by directly binding to its NACHT domain, inhibiting interactions with ASC (Zhuang et al., 2020). Other drugs, such as CY-09, act on the Walker A motif of NLRP3, displacing ATP without affecting NLRP1 or NLRC4 [108]. Analog compounds, such as N-benzyl 5-(4-sulfamoylbenzylidene-2-thioxothiazolidin-4-one), have been shown to selectively inhibit the interaction between NLRP3 and ASC, reducing inflammasome assembly [109]. Oridonin forms a covalent bond with Cys279 in the NACHT domain of NLRP3, inhibiting its interaction with NEK7 and thus reducing activation. Tetrahydroquinoline also inhibits NLRP3 inflammasome activation by binding to its NACHT domain and preventing ASC oligomerization [110]. Another compound, OLT1177, binds directly to NLRP3, inhibiting ATPase activity, caspase-1 activation, and IL-1β production in cells from patients with cryopyrin-associated periodic syndrome [111]. It showed good safety and tolerability in a Phase I trial involving patients with heart failure [112]. Other compounds, such as β-carotene, also inhibit NLRP3 inflammasome activation by binding to its PYD domain, thereby decreasing macrophage activation [113]. 4-Methylenedioxy-β-nitrostyrene inhibits NLRP3 by targeting the NACHT and LRR domains, reducing ATPase activity [114]. Lycorine binds to residues of the PYD domain, interfering with the interaction between NLRP3 and ASC [115]. Tivantinib, an anticancer agent, also inhibits the ATPase activity of NLRP3 and its assembly [116]. Bay 11–7082 inhibits inflammasome activation by alkylating cysteines in the ATPase region of NLRP3, thereby disrupting ASC pyroptosome formation [117]. However, it also inhibits IKKβ kinase activity, modulating NLRP3 expression through the NF-κB pathway [118]. Additionally, 4-hydroxynonenal disrupts the NLRP3-NEK7 interaction [119]. NIC-0102, a proteasome inhibitor, promotes polyubiquitination of NLRP3, disrupting its interaction with ASC and thereby inhibiting inflammasome activation [120]. INF39 also inhibits the interaction between NEK7 and NLRP3, blocking subsequent interactions and ASC oligomerization [121].

Inhibitors of AIM2 and NLRP3 inflammasomes

The PYD-only protein POP3 inhibits AIM2 inflammasomes by competing with ASC for recruitment (7462). Obovatol, a bisphenol compound, inhibits AIM2 and NLRP3 inflammasomes by preventing ASC pyroptosome formation [122]. RGFP966, an inhibitor of histone deacetylase 3, regulates AIM2 inflammasome activity temporally [71]. DNA aptamers have also shown promise inhibiting AIM2 inflammasome activity [123]. Roxadustat has been found to inhibit AIM2 in a CD73-dependent manner [124]. Several natural bioactive compounds also exhibit potential for inhibiting NLRP3 and AIM2 inflammasomes. For instance, costunolide, a primary active ingredient in the medicinal herb Saussurea lappa, covalently binds to Cys598 in the NACHT domain of NLRP3, inhibiting ATPase activity [125]. EFLA-945, an extract from red grapevine leaves, prevents DNA from entering macrophages, thereby reducing AIM2 inflammasome activation [126]. Ethanolic extracts from the seeds of Cornus officinalis inhibit AIM2 speck formation induced by double-stranded DNA [127].

ASC modulation

ASC is the adaptor protein in canonical inflammasomes, making it a viable target for regulating inflammasome activity. J114 inhibits the interaction between NLRP3/AIM2 and ASC, reducing ASC oligomerization [128]. Caffeic acid phenethyl ester (CAPE) binds directly to ASC and disrupts NLRP3-ASC interactions [129]. In mouse models of gouty arthritis, CAPE administration decreased caspase-1 activation and IL-1β release. Additionally, VHHASC, an alpaca-derived single-domain antibody, impairs ASC-CARD interactions while maintaining ASC's PYD function [130]. Lonidamine, a glycolysis inhibitor, inhibits ASC oligomerization by directly binding to it [131]. Dehydrocostus lactone, also from Saussurea lappa, inhibits ASC oligomerization [132]. Sulforaphane might inhibit NLRP3 inflammasome activation by affecting ASC or caspase-1 [80]. Brevilin A, derived from Centipeda minima, reduces NLRP3 inflammasome activation by blocking ASC oligomerization [133]. Additionally, 1,2,4-trimethoxybenzene, found in essential oils, inhibits ASC oligomerization and NLRP3-ASC interactions [134].

Caspase modulation

Caspase-1 inhibitors have become a key focus in the pharmaceutical industry, as caspase-1 is central to all canonical inflammasomes. VX-765 (belnacasan) selectively inhibits caspase-1 by modifying its catalytic cysteine residues and has shown potential in reducing inflammation [135]. It has also been shown to improve cognitive impairments in Alzheimer's models and preserve cardiac function in myocardial infarction, though long-term use led to hepatotoxicity in animal studies. Sennoside A, commonly used in dietary supplements, inhibits caspase-1 activity via the P2X7 pathway, reducing inflammation mediated by NLRP3 and AIM2 [132]. Pralnacasan, an orally available non-peptide compound, inhibits caspase-1, reducing joint damage in osteoarthritis models and mitigating colitis in mice [136, 137].

IL-1/IL-18 modulators

IL-1β and IL-18 are the primary pro-inflammatory cytokines activated by inflammasomes, playing critical roles in various diseases. Anakinra, a recombinant IL-1 receptor antagonist, reduces disease activity in rheumatoid arthritis (RA) patients and improves inflammatory and glycemic parameters in RA and type 2 diabetes [138]. Canakinumab, an IL-1β monoclonal antibody, is approved for treating cryopyrin-associated periodic syndromes and has been shown to reduce cardiovascular event recurrence [139, 140]. Rilonacept, another IL-1 inhibitor, has been approved for Phase 3 trials in recurrent pericarditis [141, 142]. Gevokizumab, a unique IL-1β-binding protein, is being evaluated for inflammatory diseases [143]. IL-18 blockers are also being investigated. GSK1070806, a recombinant IL-18-neutralizing antibody, showed promising results in a Phase 1 trial involving healthy and obese males [144, 145].

GSDMD modulators

Gasdermin D (GSDMD) is essential for pyroptosis, making it a significant target for treating inflammasome-related diseases. Disulfiram, an FDA-approved drug for alcoholism, inhibits GSDMD pore formation by modifying cysteine residues [146]. In mice, disulfiram reduced pyroptosis, cytokine release, and LPS-induced septic death. Necrosulfonamide and dimethyl fumarate also prevent GSDMD clustering, inhibiting pyroptosis in models of Alzheimer's disease [147]. Further research is needed to explore the potential of GSDMD inhibitors for treating inflammasome-related conditions.

Conclusion

Inflammasomes, particularly the NLRP3 inflammasome, play complex and dual roles in cancer immunity. Their activation within the tumor microenvironment influences innate immune responses and shapes adaptive immunity by modulating cytokine secretion, immune cell recruitment, and T-cell differentiation. While chronic inflammasome activation can promote tumor initiation and progression through sustained inflammation, it also presents opportunities for novel therapeutic interventions aimed at enhancing anti-tumor immunity. Recent advances have highlighted the potential of targeting inflammasome components such as sensor proteins (e.g., NLRP3, AIM2), adaptor proteins (e.g., ASC), caspase-1, and downstream cytokines IL-1β and IL-18—to modulate the immune response against cancer. Various inhibitors and modulators are under investigation, some have shown promise in preclinical studies and are currently undergoing clinical evaluation. These therapeutic strategies aim to suppress the pro-tumorigenic effects of chronic inflammation while enhancing the immune system's ability to recognize and eliminate cancer cells.

Future perspectives

Future studies should prioritize elucidating the mechanisms through which inflammasomes mediates their dual roles in tumor progression and suppression. to tumor-promoting and tumor-suppressing activities. A deeper understanding of the context-dependent roles of inflammasomes across diverse cancer types and stages could lead to the development of more precise, personalized, and effective therapeutic strategies. Additionally, investigating the interplay between inflammasome activation and other immune pathways, such as immune checkpoint blockade therapies, may uncover synergistic strategies to overcome immune resistance in tumors. Moreover, developing selective and potent inflammasome inhibitors with minimal off-target effects remains a significant challenge. Advances in drug design and delivery methods could improve these potential therapies' efficacy and safety profiles. Exploring natural compounds and bioactive agents from medicinal plants may offer alternative avenues for modulation of inflammasome. In conclusion, targeting inflammasomes represents a promising strategy to bridge innate and adaptive immune responses in cancer therapy. By harnessing the dual roles of inflammasomes, future interventions may effectively suppress tumor-promoting inflammation while activating robust anti-tumor immunity, ultimately improving clinical outcomes for cancer patients.

Data availability

No datasets were generated or analysed during the current study.

References

  1. Balkwill FR, Capasso M, Hagemann T. The tumor microenvironment at a glance. J Cell Sci. 2012;125(Pt 23):5591–6.

    Article  CAS  PubMed  Google Scholar 

  2. Moossavi M, Parsamanesh N, Bahrami A, Atkin SL, Sahebkar A. Role of the NLRP3 inflammasome in cancer. Mol Cancer. 2018;17(1):158.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Singh V, Ubaid S. Role of Silent Information Regulator 1 (SIRT1) in regulating oxidative stress and inflammation. Inflammation. 2020;43(5):1589–98.

    Article  CAS  PubMed  Google Scholar 

  4. Allavena P, Sica A, Solinas G, Porta C, Mantovani A. The inflammatory micro-environment in tumor progression: the role of tumor-associated macrophages. Crit Rev Oncol Hematol. 2008;66(1):1–9.

    Article  PubMed  Google Scholar 

  5. Singh V, Singh R, Mahdi AA, Tripathi AK. The bioengineered HALOA complex induces anoikis in chronic myeloid leukemia cells by targeting the BCR-ABL/Notch/Ikaros/Redox/Inflammation axis. J Med Life. 2022;15(5):606–16.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Qian BZ, Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell. 2010;141(1):39–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Singh V, Singh R, Kushwaha R. Exploring novel protein biomarkers for early-stage diagnosis and prognosis of T-acute lymphoblastic leukemia (T-ALL). Hematol Transfus cell Ther. 2024;24:93–S111.

  8. Jang J-H, Kim D-H, Surh Y-J. Dynamic roles of inflammasomes in inflammatory tumor microenvironment. NPJ Precis Oncol. 2021;5(1):18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. de Visser KE, Coussens LM. The inflammatory tumor microenvironment and its impact on cancer development. Contrib Microbiol. 2006;13:118–37.

    Article  PubMed  Google Scholar 

  10. Dinarello CA. Immunological and inflammatory functions of the interleukin-1 family. Annu Rev Immunol. 2009;27:519–50.

    Article  CAS  PubMed  Google Scholar 

  11. Singh V, Singh R, Kumar D, Mahdi AA, Tripathi AK. A new variant of the human α-lactalbumin-oleic acid complex as an anticancer agent for chronic myeloid leukemia. J Med Life. 2021;14(5):620–35.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Singh V, Singh R, Kushwaha R, Verma SP, Tripathi AK, Mahdi AA. The Molecular Role of HIF1α Is Elucidated in Chronic Myeloid Leukemia. Front Oncol. 2022;12: 912942.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Yao J, Sterling K, Wang Z, Zhang Y, Song W. The role of inflammasomes in human diseases and their potential as therapeutic targets. Signal Transduct Target Ther. 2024;9(1):10.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Kolb R, Liu GH, Janowski AM, Sutterwala FS, Zhang W. Inflammasomes in cancer: a double-edged sword. Protein Cell. 2014;5(1):12–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hu A, Sun L, Lin H, Liao Y, Yang H, Mao Y. Harnessing innate immune pathways for therapeutic advancement in cancer. Signal Transduct Target Ther. 2024;9(1):68.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Wu J, Sun X, Jiang P. Metabolism-inflammasome crosstalk shapes innate and adaptive immunity. Cell Chem Biol. 2024;31(5):884–903.

    Article  CAS  PubMed  Google Scholar 

  17. Schroder K, Tschopp J. The inflammasomes. Cell. 2010;140(6):821–32.

    Article  CAS  PubMed  Google Scholar 

  18. Hou J, Karin M, Sun B. Targeting cancer-promoting inflammation - have anti-inflammatory therapies come of age? Nat Rev Clin Oncol. 2021;18(5):261–79.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell. 2002;10(2):417–26.

    Article  CAS  PubMed  Google Scholar 

  20. He Y, Hara H, Núñez G. Mechanism and regulation of NLRP3 inflammasome activation. Trends Biochem Sci. 2016;41(12):1012–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Felley LE, Sharma A, Theisen E, Romero-Masters JC, Sauer JD, Gumperz JE. Human Invariant NKT Cells Induce IL-1β Secretion by Peripheral Blood Monocytes via a P2X7-Independent Pathway. J Immunol. 2016S;197(6):2455–64.

    Article  CAS  PubMed  Google Scholar 

  22. Kantono M, Guo B. Inflammasomes and cancer: the dynamic role of the inflammasome in tumor development. Front Immunol. 2017;8: 1132.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Szabo G, Csak T. Inflammasomes in liver diseases. J Hepatol. 2012;57(3):642–54.

    Article  CAS  PubMed  Google Scholar 

  24. Michallet M-C, Rota G, Maslowski K, Guarda G. Innate receptors for adaptive immunity. Curr Opin Microbiol. 2013;16(3):296–302.

    Article  CAS  PubMed  Google Scholar 

  25. Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell. 2010;140(6):805–20.

    Article  CAS  PubMed  Google Scholar 

  26. Gentile LF, Cuenca AL, Cuenca AG, Nacionales DC, Ungaro R, Efron PA, et al. Improved emergency myelopoiesis and survival in neonatal sepsis by caspase-1/11 ablation. Immunology. 2015;145(2):300–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ozaki E, Campbell M, Doyle SL. Targeting the NLRP3 inflammasome in chronic inflammatory diseases: current perspectives. J Inflamm Res. 2015;8:15–27.

    PubMed  PubMed Central  Google Scholar 

  28. Eigenbrod T, Dalpke AH. Bacterial RNA: an underestimated stimulus for innate immune responses. J Immunol. 2015;195(2):411–8.

    Article  CAS  PubMed  Google Scholar 

  29. Amarante-Mendes GP, Adjemian S, Branco LM, Zanetti LC, Weinlich R, Bortoluci KR. Pattern recognition receptors and the host cell death molecular machinery. Front Immunol. 2018;9: 2379.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Choi EH, Kim MH, Park SJ. Targeting mitochondrial dysfunction and reactive oxygen species for neurodegenerative disease treatment. Int J Mol Sci. 2024;25(14):7952.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Quadiri A, Kalia I, Kashif M, Singh AP. Identification and characterization of protective CD8+ T-epitopes in a malaria vaccine candidate SLTRiP. Immunity Inflamm Dis. 2020;8(1):50–61.

    Article  CAS  Google Scholar 

  32. Olona A, Leishman S, Anand PK. The NLRP3 inflammasome: regulation by metabolic signals. Trends Immunol. 2022;43(12):978–89.

    Article  CAS  PubMed  Google Scholar 

  33. Kashif M, Quadiri A, Singh AP. Essential role of a Plasmodium berghei heat shock protein (PBANKA_0938300) in gametocyte development. Sci Rep. 2021;11(1):23640.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Gupta Y, Sharma N, Singh S, Romero JG, Rajendran V, Mogire RM, et al. The Multistage Antimalarial Compound Calxinin Perturbates P. falciparum Ca2+ Homeostasis by Targeting a Unique Ion Channel. Pharmaceutics. 2022;14(7):1371.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Guo H, Callaway JB, Ting JPY. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med. 2015;21(7):677–87.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Sugimoto MA, Sousa LP, Pinho V, Perretti M, Teixeira MM. Resolution of Inflammation: What Controls Its Onset? Front Immunol. 2016;7:160.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Pelegrin P, Surprenant A. Dynamics of macrophage polarization reveal new mechanism to inhibit IL-1beta release through pyrophosphates. EMBO J. 2009;28(14):2114–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Loher F, Bauer C, Landauer N, Schmall K, Siegmund B, Lehr HA, et al. The interleukin-1 beta-converting enzyme inhibitor pralnacasan reduces dextran sulfate sodium-induced murine colitis and T helper 1 T-cell activation. J Pharmacol Exp Ther. 2004;308(2):583–90.

    Article  CAS  PubMed  Google Scholar 

  39. Ruscitti P, Berardicurti O, Cipriani P, Giacomelli R, TRACK study group. Benefits of anakinra versus TNF inhibitors in rheumatoid arthritis and type 2 diabetes: long-term findings from participants furtherly followed-up in the TRACK study, a multicentre, open-label, randomised, controlled trial. Clin Exp Rheumatol. 2021;39(2):403–6.

    Article  PubMed  Google Scholar 

  40. Hosono K, Kato C, Sasajima T. Real-world safety and effectiveness of canakinumab in patients with cryopyrin-associated periodic fever syndrome: a long-term observational study in Japan. Clin Exp Rheumatol. 2022;40(8):1543–53.

    PubMed  Google Scholar 

  41. Everett BM, MacFadyen JG, Thuren T, Libby P, Glynn RJ, Ridker PM. Inhibition of Interleukin-1β and Reduction in Atherothrombotic Cardiovascular Events in the CANTOS Trial. J Am Coll Cardiol. 2020;76(14):1660–70.

    Article  CAS  PubMed  Google Scholar 

  42. Schumacher HR, Evans RR, Saag KG, Clower J, Jennings W, Weinstein SP, et al. Rilonacept (interleukin-1 trap) for prevention of gout flares during initiation of uric acid-lowering therapy: results from a phase III randomized, double-blind, placebo-controlled, confirmatory efficacy study. Arthritis Care Res (Hoboken). 2012;64(10):1462–70.

    Article  CAS  PubMed  Google Scholar 

  43. Klein AL, Imazio M, Cremer P, Brucato A, Abbate A, Fang F, et al. Phase 3 trial of interleukin-1 trap rilonacept in recurrent pericarditis. N Engl J Med. 2021;384(1):31–41.

    Article  CAS  PubMed  Google Scholar 

  44. Issafras H, Corbin JA, Goldfine ID, Roell MK. Detailed mechanistic analysis of gevokizumab, an allosteric anti-IL-1β antibody with differential receptor-modulating properties. J Pharmacol Exp Ther. 2014;348(1):202–15.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Wlodek E, Kirkpatrick RB, Andrews S, Noble R, Schroyer R, Scott J, et al. A pilot study evaluating GSK1070806 inhibition of interleukin-18 in renal transplant delayed graft function. PLoS ONE. 2021;16(3): e0247972.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Mistry P, Reid J, Pouliquen I, McHugh S, Abberley L, DeWall S, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of single-dose antiinterleukin- 18 mAb GSK1070806 in healthy and obese subjects. Int J Clin Pharmacol Ther. 2014;52(10):867–79.

    Article  CAS  PubMed  Google Scholar 

  47. Hu JJ, Liu X, Xia S, Zhang Z, Zhang Y, Zhao J, et al. FDA-approved disulfiram inhibits pyroptosis by blocking gasdermin D pore formation. Nat Immunol. 2020;21(7):736–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Han C, Yang Y, Guan Q, Zhang X, Shen H, Sheng Y, et al. New mechanism of nerve injury in Alzheimer’s disease: β-amyloid-induced neuronal pyroptosis. J Cell Mol Med. 2020;24(14):8078–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Lv T, Xiong X, Yan W, Liu M, Xu H, He Q. Targeting of GSDMD sensitizes HCC to anti-PD-1 by activating cGAS pathway and downregulating PD-L1 expression. J Immunother Cancer. 2022;10(6):e004763.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Veglia F, Perego M, Gabrilovich D. Myeloid-derived suppressor cells coming of age. Nat Immunol. 2018;19(2):108–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Li S, Liang X, Ma L, Shen L, Li T, Zheng L, et al. MiR-22 sustains NLRP3 expression and attenuates H. pylori-induced gastric carcinogenesis. Oncogene. 2018;37(7):884–96.

    Article  CAS  PubMed  Google Scholar 

  52. Pontillo A, Bricher P, Leal VNC, Lima S, Souza PRE, Crovella S. Role of inflammasome genetics in susceptibility to HPV infection and cervical cancer development. J Med Virol. 2016;88(9):1646–51.

    Article  CAS  PubMed  Google Scholar 

  53. Weichand B, Popp R, Dziumbla S, Mora J, Strack E, Elwakeel E, et al. S1PR1 on tumor-associated macrophages promotes lymphangiogenesis and metastasis via NLRP3/IL-1β. J Exp Med. 2017;214(9):2695–713.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Ershaid N, Sharon Y, Doron H, Raz Y, Shani O, Cohen N, et al. NLRP3 inflammasome in fibroblasts links tissue damage with inflammation in breast cancer progression and metastasis. Nat Commun. 2019;10(1):4375.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Deng Q, Geng Y, Zhao L, Li R, Zhang Z, Li K, et al. NLRP3 inflammasomes in macrophages drive colorectal cancer metastasis to the liver. Cancer Lett. 2019;1(442):21–30.

    Article  Google Scholar 

  56. Aranda F, Chaba K, Bloy N, Garcia P, Bordenave C, Martins I, et al. Immune effectors responsible for the elimination of hyperploid cancer cells. Oncoimmunology. 2018;7(8): e1463947.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Lee HE, Lee JY, Yang G, Kang HC, Cho YY, Lee HS, et al. Inhibition of NLRP3 inflammasome in tumor microenvironment leads to suppression of metastatic potential of cancer cells. Sci Rep. 2019;9(1):12277.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Daley D, Mani VR, Mohan N, Akkad N, Pandian GSDB, Savadkar S, et al. NLRP3 signaling drives macrophage-induced adaptive immune suppression in pancreatic carcinoma. J Exp Med. 2017;214(6):1711–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Romero JM, Grünwald B, Jang GH, Bavi PP, Jhaveri A, Masoomian M, et al. A four-chemokine signature is associated with a T-cell-Inflamed phenotype in primary and metastatic pancreatic cancer. Clin Cancer Res. 2020;26(8):1997–2010.

    Article  CAS  PubMed  Google Scholar 

  60. Zhiyu W, Wang N, Wang Q, Peng C, Zhang J, Liu P, et al. The inflammasome: an emerging therapeutic oncotarget for cancer prevention. Oncotarget. 2016;7(31):50766–80.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Dupaul-Chicoine J, Arabzadeh A, Dagenais M, Douglas T, Champagne C, Morizot A, et al. The Nlrp3 inflammasome suppresses colorectal cancer metastatic growth in the liver by promoting natural killer cell tumoricidal activity. Immunity. 2015;43(4):751–63.

    Article  CAS  PubMed  Google Scholar 

  62. Chen L, Huang C-F, Li Y-C, Deng W-W, Mao L, Wu L, et al. Blockage of the NLRP3 inflammasome by MCC950 improves anti-tumor immune responses in head and neck squamous cell carcinoma. Cell Mol Life Sci. 2018;75(11):2045–58.

    Article  CAS  PubMed  Google Scholar 

  63. Chen LC, Wang LJ, Tsang NM, Ojcius DM, Chen CC, Ouyang CN, et al. Tumour inflammasome-derived IL-1β recruits neutrophils and improves local recurrence-free survival in EBV-induced nasopharyngeal carcinoma. EMBO Mol Med. 2012;4(12):1276–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Kaur BP, Secord E. Innate Immunity. Immunol Allergy Clin North Am. 2021;41(4):535–41.

    Article  PubMed  Google Scholar 

  65. Rehman AU, Iqbal MA, Sattar RSA, Saikia S, Kashif M, Ali WM, et al. Elevated expression of RUNX3 co-expressing with EZH2 in esophageal cancer patients from India. Cancer Cell Int. 2020;20:445.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Palucka AK, Coussens LM. The Basis of Oncoimmunology. Cell. 2016;164(6):1233–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Netea MG, Balkwill F, Chonchol M, Cominelli F, Donath MY, Giamarellos-Bourboulis EJ, et al. A guiding map for inflammation. Nat Immunol. 2017;18(8):826–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Wang J. Neutrophils in tissue injury and repair. Cell Tissue Res. 2018;371(3):531–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Headland SE, Norling LV. The resolution of inflammation: Principles and challenges. Semin Immunol. 2015;27(3):149–60.

    Article  CAS  PubMed  Google Scholar 

  70. Nathan C, Ding A. Nonresolving inflammation. Cell. 2010;140(6):871–82.

    Article  CAS  PubMed  Google Scholar 

  71. Dvorak HF. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med. 1986;315(26):1650–9.

    Article  CAS  PubMed  Google Scholar 

  72. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140(6):883–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Quadiri A, Prakash S, Dhanushkodi NR, Singer M, Zayou L, Shaik AM, et al. Therapeutic prime/pull vaccination of HSV-2 infected guinea pigs with the ribonucleotide reductase 2 (RR2) protein and CXCL11 chemokine boosts antiviral local tissue-resident and effector memory CD4+ and CD8+ T cells and protects against recurrent genital Herpes. J Virol. 2024;14;98(5):e0159623.

  74. Moore PS, Chang Y. Why do viruses cause cancer? Highlights of the first century of human tumour virology. Nat Rev Cancer. 2010;10(12):878–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Hegde S, Krisnawan VE, Herzog BH, Zuo C, Breden MA, Knolhoff BL, et al. Dendritic cell paucity leads to dysfunctional immune surveillance in pancreatic cancer. Cancer Cell. 2020;37(3):289-307.e9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Wynn TA, Chawla A, Pollard JW. Macrophage biology in development, homeostasis and disease. Nature. 2013;496(7446):445–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Gentles AJ, Newman AM, Liu CL, Bratman SV, Feng W, Kim D, et al. The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat Med. 2015;21(8):938–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Liew PX, Kubes P. The neutrophil’s role during health and disease. Physiol Rev. 2019;99(2):1223–48.

    Article  CAS  PubMed  Google Scholar 

  79. Wellenstein MD, Coffelt SB, Duits DEM, van Miltenburg MH, Slagter M, de Rink I, et al. Loss of p53 triggers WNT-dependent systemic inflammation to drive breast cancer metastasis. Nature. 2019;572(7770):538–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Steinman RM. The dendritic cell system and its role in immunogenicity. Annu Rev Immunol. 1991;9:271–96.

    Article  CAS  PubMed  Google Scholar 

  81. Villadangos JA, Schnorrer P. Intrinsic and cooperative antigen-presenting functions of dendritic-cell subsets in vivo. Nat Rev Immunol. 2007;7(7):543–55.

    Article  CAS  PubMed  Google Scholar 

  82. Serhan CN, Savill J. Resolution of inflammation: the beginning programs the end. Nat Immunol. 2005;6(12):1191–7.

    Article  CAS  PubMed  Google Scholar 

  83. Zhang J, Liu X, Wan C, Liu Y, Wang Y, Meng C, et al. NLRP3 inflammasome mediates M1 macrophage polarization and IL-1β production in inflammatory root resorption. J Clin Periodontol. 2020;47(4):451–60.

    Article  CAS  PubMed  Google Scholar 

  84. Lu J, Xie S, Deng Y, Xie X, Liu Y. Blocking the NLRP3 inflammasome reduces osteogenic calcification and M1 macrophage polarization in a mouse model of calcified aortic valve stenosis. Atherosclerosis. 2022;347:28–38.

    Article  CAS  PubMed  Google Scholar 

  85. Xia D-Y, Yuan J-L, Jiang X-C, Qi M, Lai N-S, Wu L-Y, et al. SIRT1 Promotes M2 Microglia Polarization via Reducing ROS-Mediated NLRP3 Inflammasome Signaling After Subarachnoid Hemorrhage. Front Immunol. 2021;12: 770744.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Khare S, Ratsimandresy RA, de Almeida L, Cuda CM, Rellick SL, Misharin AV, et al. The PYRIN domain-only protein POP3 inhibits ALR inflammasomes and regulates responses to infection with DNA viruses. Nat Immunol. 2014;15(4):343–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Hatscher L, Lehmann CHK, Purbojo A, Onderka C, Liang C, Hartmann A, et al. Select hyperactivating NLRP3 ligands enhance the TH1- and TH17-inducing potential of human type 2 conventional dendritic cells. Sci Signal. 2021;14(680):eabe1757.

  88. Zhang X, Chen S, Song L, Tang Y, Shen Y, Jia L, et al. MTOR-independent, autophagic enhancer trehalose prolongs motor neuron survival and ameliorates the autophagic flux defect in a mouse model of amyotrophic lateral sclerosis. Autophagy. 2014;10(4):588–602.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Rühl S, Shkarina K, Demarco B, Heilig R, Santos JC, Broz P. ESCRT-dependent membrane repair negatively regulates pyroptosis downstream of GSDMD activation. Science. 2018;362(6417):956–60.

    Article  PubMed  Google Scholar 

  90. Pruenster M, Immler R, Roth J, Kuchler T, Bromberger T, Napoli M, et al. E-selectin-mediated rapid NLRP3 inflammasome activation regulates S100A8/S100A9 release from neutrophils via transient gasdermin D pore formation. Nat Immunol. 2023;24(12):2021–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Karmakar M, Minns M, Greenberg EN, Diaz-Aponte J, Pestonjamasp K, Johnson JL, et al. N-GSDMD trafficking to neutrophil organelles facilitates IL-1β release independently of plasma membrane pores and pyroptosis. Nat Commun. 2020;11(1):2212.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Münzer P, Negro R, Fukui S, di Meglio L, Aymonnier K, Chu L, et al. NLRP3 Inflammasome Assembly in Neutrophils Is Supported by PAD4 and Promotes NETosis Under Sterile Conditions. Front Immunol. 2021;12: 683803.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Ali MF, Dasari H, Van Keulen VP, Carmona EM. Canonical Stimulation of the NLRP3 Inflammasome by Fungal Antigens Links Innate and Adaptive B-Lymphocyte Responses by Modulating IL-1β and IgM Production. Front Immunol. 2017;8:1504.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Camell CD, Günther P, Lee A, Goldberg EL, Spadaro O, Youm Y-H, et al. Aging Induces an Nlrp3 Inflammasome-Dependent Expansion of Adipose B Cells That Impairs Metabolic Homeostasis. Cell Metab. 2019Dec 3;30(6):1024-1039.e6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Gulen MF, Koch U, Haag SM, Schuler F, Apetoh L, Villunger A, et al. Signalling strength determines proapoptotic functions of STING. Nat Commun. 2017;8(1):427.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Pietschmann K, Beetz S, Welte S, Martens I, Gruen J, Oberg HH, et al. Toll-like receptor expression and function in subsets of human gammadelta T lymphocytes. Scand J Immunol. 2009;70(3):245–55.

    Article  CAS  PubMed  Google Scholar 

  97. Whiteside SK, Snook JP, Williams MA, Weis JJ. Bystander T cells: a balancing act of friends and foes. Trends Immunol. 2018;39(12):1021–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Ben-Sasson SZ, Wang K, Cohen J, Paul WE. IL-1β strikingly enhances antigen-driven CD4 and CD8 T-cell responses. Cold Spring Harb Symp Quant Biol. 2013;78:117–24.

    Article  CAS  PubMed  Google Scholar 

  99. Zayou L, Prakash S, Dhanushkodi NR, Quadiri A, Ibraim IC, Singer M, et al. A multi-epitope/CXCL11 prime/pull coronavirus mucosal vaccine boosts the frequency and the function of lung-resident memory CD4+ and CD8+ T cells and enhanced protection against COVID-19-like symptoms and death caused by SARS-CoV-2 infection. J Virol. 2023;97(12):e0109623.

    Article  PubMed  Google Scholar 

  100. Prakash S, Dhanushkodi NR, Zayou L, Ibraim IC, Quadiri A, Coulon PG, et al. Cross-protection induced by highly conserved human B, CD4+, and CD8+ T-cell epitopes-based vaccine against severe infection, disease, and death caused by multiple SARS-CoV-2 variants of concern. Front Immunol. 2024;15:1328905.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Dinarello CA. IL-18: A TH1-inducing, proinflammatory cytokine and new member of the IL-1 family. J Allergy Clin Immunol. 1999;103(1 Pt 1):11–24.

    Article  CAS  PubMed  Google Scholar 

  102. Phulphagar K, Kühn LI, Ebner S, Frauenstein A, Swietlik JJ, Rieckmann J, et al. Proteomics reveals distinct mechanisms regulating the release of cytokines and alarmins during pyroptosis. Cell Rep. 2021;34(10):108826.

    Article  CAS  PubMed  Google Scholar 

  103. Lu B, Wang H, Andersson U, Tracey KJ. Regulation of HMGB1 release by inflammasomes. Protein Cell. 2013;4(3):163–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Lamkanfi M, Sarkar A, Vande Walle L, Vitari AC, Amer AO, Wewers MD, et al. Inflammasome-dependent release of the alarmin HMGB1 in endotoxemia. J Immunol. 2010;185(7):4385–92.

    Article  CAS  PubMed  Google Scholar 

  105. Volchuk A, Ye A, Chi L, Steinberg BE, Goldenberg NM. Indirect regulation of HMGB1 release by gasdermin D. Nat Commun. 2020;11(1):4561.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Yao Y, Chen S, Cao M, Fan X, Yang T, Huang Y, et al. Antigen-specific CD8+ T cell feedback activates NLRP3 inflammasome in antigen-presenting cells through perforin. Nat Commun. 2017;24(8):15402.

    Article  Google Scholar 

  107. Theivanthiran B, Evans KS, DeVito NC, Plebanek M, Sturdivant M, Wachsmuth LP, et al. A tumor-intrinsic PD-L1/NLRP3 inflammasome signaling pathway drives resistance to anti-PD-1 immunotherapy. J Clin Invest. 2020;130(5):2570–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Vandana, Shankar S, Prasad KM, Kashif M, Kalia I, Rai R, et al. A nonpeptidyl molecule modulates apoptosis-like cell death by inhibiting P. falciparum metacaspase-2. Biochem J. 2020;477(7):1323–44.

  109. Anand R, Kashif M, Pandit A, Babu R, Singh AP. Reprogramming in candida albicans gene expression network under butanol stress abrogates hyphal development. Int J Mol Sci. 2023;24(24):17227.

  110. Guarda G, Dostert C, Staehli F, Cabalzar K, Castillo R, Tardivel A, et al. T cells dampen innate immune responses through inhibition of NLRP1 and NLRP3 inflammasomes. Nature. 2009;460(7252):269–73.

    Article  CAS  PubMed  Google Scholar 

  111. Sharma PK, Kalia I, Kaushik V, Brünnert D, Quadiri A, Kashif M, et al. STK35L1 regulates host cell cycle-related genes and is essential for Plasmodium infection during the liver stage of malaria. Exp Cell Res. 2021;406(2):112764.

    Article  CAS  PubMed  Google Scholar 

  112. Yao Y, Vent-Schmidt J, McGeough MD, Wong M, Hoffman HM, Steiner TS, et al. Tr1 Cells, but Not Foxp3+ Regulatory T Cells, Suppress NLRP3 Inflammasome Activation via an IL-10-Dependent Mechanism. J Immunol. 2015;195(2):488–97.

    Article  CAS  PubMed  Google Scholar 

  113. Ip WKE, Hoshi N, Shouval DS, Snapper S, Medzhitov R. Anti-inflammatory effect of IL-10 mediated by metabolic reprogramming of macrophages. Science. 2017;356(6337):513–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Guarda G, Braun M, Staehli F, Tardivel A, Mattmann C, Förster I, et al. Type I interferon inhibits interleukin-1 production and inflammasome activation. Immunity. 2011;34(2):213–23.

    Article  CAS  PubMed  Google Scholar 

  115. Chow MT, Duret H, Andrews DM, Faveeuw C, Möller A, Smyth MJ, et al. Type I NKT-cell-mediated TNF-α is a positive regulator of NLRP3 inflammasome priming. Eur J Immunol. 2014;44(7):2111–20.

    Article  CAS  PubMed  Google Scholar 

  116. Sharif H, Hollingsworth LR, Griswold AR, Hsiao JC, Wang Q, Bachovchin DA, et al. Dipeptidyl peptidase 9 sets a threshold for CARD8 inflammasome formation by sequestering its active C-terminal fragment. Immunity. 2021;54(7):1392-1404.e10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Hollingsworth LR, Sharif H, Griswold AR, Fontana P, Mintseris J, Dagbay KB, et al. DPP9 sequesters the C terminus of NLRP1 to repress inflammasome activation. Nature. 2021;592(7856):778–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Coll RC, Hill JR, Day CJ, Zamoshnikova A, Boucher D, Massey NL, et al. MCC950 directly targets the NLRP3 ATP-hydrolysis motif for inflammasome inhibition. Nat Chem Biol. 2019;15(6):556–9.

    Article  CAS  PubMed  Google Scholar 

  119. Jiang H, He H, Chen Y, Huang W, Cheng J, Ye J, et al. Identification of a selective and direct NLRP3 inhibitor to treat inflammatory disorders. J Exp Med. 2017;214(11):3219–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Zuo D, Do N, Hwang I, Ann J, Yu JW, Lee J. Design and synthesis of an N-benzyl 5-(4-sulfamoylbenzylidene-2-thioxothiazolidin-4-one scaffold as a novel NLRP3 inflammasome inhibitor. Bioorg Med Chem Lett. 2022;65:128693.

    Article  CAS  PubMed  Google Scholar 

  121. Dai Z, Chen XY, An LY, Li CC, Zhao N, Yang F, et al. Development of Novel Tetrahydroquinoline Inhibitors of NLRP3 Inflammasome for Potential Treatment of DSS-Induced Mouse Colitis. J Med Chem. 2021;64(1):871–89.

    Article  CAS  PubMed  Google Scholar 

  122. Marchetti C, Swartzwelter B, Gamboni F, Neff CP, Richter K, Azam T, et al. OLT1177, a β-sulfonyl nitrile compound, safe in humans, inhibits the NLRP3 inflammasome and reverses the metabolic cost of inflammation. Proc Natl Acad Sci U S A. 2018;115(7):E1530–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Wohlford GF, Van Tassell BW, Billingsley HE, Kadariya D, Canada JM, Carbone S, et al. Phase 1B, randomized, double-blinded, dose escalation, single-center, repeat dose safety and pharmacodynamics study of the oral nlrp3 inhibitor dapansutrile in subjects with nyha ii-iii systolic heart failure. J Cardiovasc Pharmacol. 2020;77(1):49–60.

    Article  PubMed  PubMed Central  Google Scholar 

  124. Yang G, Lee HE, Moon S-J, Ko KM, Koh JH, Seok JK, et al. Direct Binding to NLRP3 Pyrin Domain as a Novel Strategy to Prevent NLRP3-Driven Inflammation and Gouty Arthritis. Arthritis Rheumatol (Hoboken, NJ). 2020;72(7):1192–202.

    Article  CAS  Google Scholar 

  125. He Y, Varadarajan S, Muñoz-Planillo R, Burberry A, Nakamura Y, Núñez G. 3,4-methylenedioxy-β-nitrostyrene inhibits NLRP3 inflammasome activation by blocking assembly of the inflammasome. J Biol Chem. 2014;289(2):1142–50.

    Article  CAS  PubMed  Google Scholar 

  126. Liang Q, Cai W, Zhao Y, Xu H, Tang H, Chen D, et al. Lycorine ameliorates bleomycin-induced pulmonary fibrosis via inhibiting NLRP3 inflammasome activation and pyroptosis. Pharmacol Res. 2020;158:104884.

    Article  CAS  PubMed  Google Scholar 

  127. Huang Y, Guo Y, Zhou Y, Huang Q, Ru Y, Luo Y, et al. Tivantinib alleviates inflammatory diseases by directly targeting NLRP3. iScience. 2023;26(3):106062.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Juliana C, Fernandes-Alnemri T, Wu J, Datta P, Solorzano L, Yu JW, et al. Anti-inflammatory compounds parthenolide and Bay 11–7082 are direct inhibitors of the inflammasome. J Biol Chem. 2010;285(13):9792–802.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Lee J, Rhee MH, Kim E, Cho JY. BAY 11–7082 is a broad-spectrum inhibitor with anti-inflammatory activity against multiple targets. Mediators Inflamm. 2012;2012: 416036.

    Article  PubMed  PubMed Central  Google Scholar 

  130. Hsu CG, Chávez CL, Zhang C, Sowden M, Yan C, Berk BC. The lipid peroxidation product 4-hydroxynonenal inhibits NLRP3 inflammasome activation and macrophage pyroptosis. Cell Death Differ. 2022;29(9):1790–803.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Wu J, Lan Y, Shi X, Huang W, Li S, Zhang J, et al. Sennoside A is a novel inhibitor targeting caspase-1. Food Funct. 2022;13(19):9782–95.

    Article  CAS  PubMed  Google Scholar 

  132. Shi Y, Lv Q, Zheng M, Sun H, Shi F. NLRP3 inflammasome inhibitor INF39 attenuated NLRP3 assembly in macrophages. Int Immunopharmacol. 2021;92:107358.

    Article  CAS  PubMed  Google Scholar 

  133. Kim J, Ahn H, Han BC, Shin H, Kim JC, Jung EM, et al. Obovatol inhibits NLRP3, AIM2, and non-canonical inflammasome activation. Phytomedicine. 2019;63:153019.

    Article  CAS  PubMed  Google Scholar 

  134. Ni X, Castanares M, Mukherjee A, Lupold SE. Nucleic acid aptamers: clinical applications and promising new horizons. Curr Med Chem. 2011;18(27):4206–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Yang H, Wu Y, Cheng M, Zhang M, Qiu X, Liu S, et al. Roxadustat (FG-4592) protects against ischaemia-induced acute kidney injury via improving CD73 and decreasing AIM2 inflammasome activation. Nephrol Dial Transplant. 2023;38(4):858–75.

    Article  CAS  PubMed  Google Scholar 

  136. Xu H, Chen J, Chen P, Li W, Shao J, Hong S, et al. Costunolide covalently targets NACHT domain of NLRP3 to inhibit inflammasome activation and alleviate NLRP3-driven inflammatory diseases. Acta Pharm Sin B. 2023;13(2):678–93.

    Article  CAS  PubMed  Google Scholar 

  137. Chung IC, Yuan SN, OuYang CN, Hu SI, Lin HC, Huang KY, et al. EFLA 945 restricts AIM2 inflammasome activation by preventing DNA entry for psoriasis treatment. Cytokine. 2020;127:154951.

    Article  CAS  PubMed  Google Scholar 

  138. Lee SB, Kang JH, Sim EJ, Jung YR, Kim JH, Hillman PF, et al. Cornus officinalis seed extract inhibits AIM2-Inflammasome activation and attenuates imiquimod-induced psoriasis-like skin inflammation. Int J Mol Sci. 2023;24(6):5653.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Jiao Y, Nan J, Mu B, Zhang Y, Zhou N, Yang S, et al. Discovery of a novel and potent inhibitor with differential species-specific effects against NLRP3 and AIM2 inflammasome-dependent pyroptosis. Eur J Med Chem. 2022;15(232):114194.

    Article  Google Scholar 

  140. Lee HE, Yang G, Kim ND, Jeong S, Jung Y, Choi JY, et al. Targeting ASC in NLRP3 inflammasome by caffeic acid phenethyl ester: a novel strategy to treat acute gout. Sci Rep. 2016;9(6):38622.

    Article  Google Scholar 

  141. Schmidt FI, Lu A, Chen JW, Ruan J, Tang C, Wu H, et al. A single domain antibody fragment that recognizes the adaptor ASC defines the role of ASC domains in inflammasome assembly. J Exp Med. 2016;213(5):771–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Chen C, Zhou Y, Ning X, Li S, Xue D, Wei C, et al. Directly targeting ASC by lonidamine alleviates inflammasome-driven diseases. J Neuroinflammation. 2022;19(1):315.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Chen Y, Li R, Wang Z, Hou X, Wang C, Ai Y, et al. Dehydrocostus lactone inhibits NLRP3 inflammasome activation by blocking ASC oligomerization and prevents LPS-mediated inflammation in vivo. Cell Immunol. 2020;349:104046.

    Article  CAS  PubMed  Google Scholar 

  144. Qin Q, Xu G, Zhan X, Wang Z, Wang Y, Liu H, et al. Brevilin A inhibits NLRP3 inflammasome activation in vivo and in vitro by acting on the upstream of NLRP3-induced ASC oligomerization. Mol Immunol. 2021;135:116–26.

    Article  CAS  PubMed  Google Scholar 

  145. Liao YJ, Pan RY, Kong XX, Cheng Y, Du L, Wang ZC, et al. Correction: 1,2,4-Trimethoxybenzene selectively inhibits NLRP3 inflammasome activation and attenuates experimental autoimmune encephalomyelitis. Acta Pharmacol Sin. 2022;43(2):504.

    Article  CAS  PubMed  Google Scholar 

  146. Flores J, Fillion ML, LeBlanc AC. Caspase-1 inhibition improves cognition without significantly altering amyloid and inflammation in aged Alzheimer disease mice. Cell Death Dis. 2022;13(10):864.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Rudolphi K, Gerwin N, Verzijl N, van der Kraan P, van den Berg W. Pralnacasan, an inhibitor of interleukin-1beta converting enzyme, reduces joint damage in two murine models of osteoarthritis. Osteoarthr Cartil. 2003;11(10):738–46.

    Article  CAS  Google Scholar 

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Acknowledgements

Elements of Figs. 1, 2, 3, 4, and 5 were created with BioRender.com. The authors thank Yolanda L. Jones, National Institutes of Health (NIH), Library Editing Services, for manuscript editing assistance.

The authors thank Yolanda L. Jones, National Institutes of Health (NIH), Library Editing Services, for manuscript editing assistance.

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  1. Vivek Singh, Saba Ubaid and Mohammad Kashif contributed equally to this work.

Authors and Affiliations

  1. Thoracic Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA

    Vivek Singh & Anand Singh

  2. Department of Biochemistry, King George’S Medical University (KGMU), U.P, Lucknow, 226003, India

    Saba Ubaid, Tanvi Singh & Gaurav Singh

  3. Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA

    Mohammad Kashif

  4. Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA

    Roma Pahwa

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VS, SU, MK, TS, GS, and RP: conducted the article search, interpreted the data, writing of text and table, drawing figure, and editing. AS, VS: conceived the ideas and proposed the scope. AS: writing, revision and editing, study design and direction. All authors read the article and approved the submitted version.

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Singh, V., Ubaid, S., Kashif, M. et al. Role of inflammasomes in cancer immunity: mechanisms and therapeutic potential. J Exp Clin Cancer Res 44, 109 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13046-025-03366-y

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Journal of Experimental & Clinical Cancer Research

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