The role of the inflammasome in cancer promotion is often mediated by IL-1β, which is produced by various cells in the tumor, including tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs). Indeed, myeloid- or CAF-specific deletion of genes involved in Nlrp3 inflammasome activation leads to decreased tumor growth. For example, the sphingolipid sphingosine-1-phosphate (S1P) receptor was shown to activate the Nlrp3 inflammasome in TAMs, and myeloid-specific deletion of S1pr reduced IL-1β-driven lymphangiogenesis and pulmonary metastasis in the polyoma middle T (PyMT) mouse model of breast cancer (Weichand et al., 2017). Using the same model, Ershaid et al. showed that CAF-specific genetic ablation of Nlrp3 or Il1b delayed tumor growth and attenuated lung metastasis (Ershaid et al., 2019). Mechanistically, IL-1β promoted tumor progression and metastasis by driving an immunosuppressive tumor microenvironment (TME) and inducing the expression of adhesion molecules on endothelial cells (Ershaid et al., 2019). Furthermore, Nlrp3 inflammasome-mediated IL-1β was shown to induce the production of the cancer-promoting cytokine IL-22 by memory CD4⁺ T cells. This was demonstrated in models of breast and lung cancers in which neutralization of IL-1R signaling with anakinra abrogated IL-22 production and reduced tumor growth (Voigt et al., 2017). IL-1β produced by TAMs or released from cancer cells can also boost the pro-tumorigenic activity of CAFs, highlighting its role as a master orchestrator of tumorigenesis (Brunetto et al., 2019). Besides its effects on the TME, IL-1β autocrine signaling was shown to act as a direct driver of cancer cell proliferation. This was demonstrated using the diethylnitrosamine (DEN) mouse model of hepatocellular carcinoma (HCC), in which the mitophagy effector FUNDC1 was specifically deleted in hepatocytes leading to aberrant activation of the Nlrp3 inflammasome and IL-1β-driven hepatocyte hyperproliferation (Wenhui Li et al., 2019). This was also reported in a mouse model of AML driven by the oncogenic Kras^G12D pathway which activated the Nlrp3 inflammasome via Kras-RAC1-induced ROS production. Nlrp3 deletion reduced abnormal myeloproliferation and restored normal hematopoiesis (Hamarsheh et al., 2020). In addition to inducing proliferation and survival of cancer cells, IL-1β can also favor their migration and invasion. In a colorectal cancer (CRC) model, macrophage-derived IL-1β was shown to elicit the production of serum amyloid A1 (SAA1) by tumor cells, which in a feed-forward manner induced macrophages to upregulate metalloproteinase-9 secretion allowing cancer migration and establishment of metastasis (Sudo et al., 2021) (Figure 2A). Whereas the bulk of the evidence point to IL-1β as the main driver of inflammasome tumor-promoting effects, a recent study by Hofbauer et al., studying multiple myeloma in a murine model, described a role of Nlrp3-dependent IL-18 in bone destruction and multiple myeloma proliferation (Hofbauer et al., 2021).

Last, inflammasome-independent functions in tumor promotion have been reported. Qi et al. showed that while polydA:dT stimulation of three NSCLC cell-lines activated the AIM2 inflammasome, it did not have an impact on their growth or survival. In contrast, AIM2 promoted NSCLC tumor growth in vivo by regulating mitochondrial fusion dynamics and ERK activation (Qi et al., 2020).

In response to tissue damage, select inflammatory cytokines promote the repair process. When this response is aberrant, as in the context of chronic inflammation, excessive tissue repair can lead to neoplastic growth. This is best illustrated in colitis-associated CRC and HCC. We and others have shown early on that inflammasome-dependent IL-18 production is necessary for intestinal tissue repair in mouse models of colitis and that excessive inflammasome signaling promoted intestinal tumorigenesis [reviewed in (Saleh and Trinchieri, 2011)]. Huber et al. later showed that IL-18 promoted the biological activity of IL-22, an important reparative cytokine, by inhibiting the production of IL-22-binding protein (IL-22BP), a soluble form of the IL-22 receptor and a negative regulator of IL-22 (Figure 2B). Knock-out of Il22bp which resulted in increased IL-22/IL-22BP ratio accelerated tumorigenesis in the dextran sulfate sodium (DSS)-azoxymethane (AOM) colitis-associated CRC mouse model as well as in Apc ^min/+ mice that develop intestinal adenomas (Huber et al., 2012). Besides IL-18, excessive IL-1β production in the gut drives IL-17 production by CD4⁺ Th17 cells and innate lymphocytes (ILC) 3, that recruit granulocytes and trigger intestinal inflammation (Coccia et al., 2012). More recently, Dmitrieva-Posocco O et al. demonstrated cell-type specific function of IL-1 signaling in intestinal tumorigenesis. Whereas T cell-specific deletion of Il1ra reduced IL-17A/IL-22-dependent tumorigenesis, Il1ra ablation in neutrophils impaired their function in bacterial control, leading to microbial tumor invasion, which elicited exacerbated inflammation and CRC (Dmitrieva-Posocco et al., 2019). As in CRC, chronic inflammation and cirrhosis induced by liver injury predispose to HCC. The AIM2 inflammasome was reported to be activated in patients with advanced cirrhosis, particularly in macrophages of the ascites (Lozano-Ruiz et al., 2015) (Figure 2B). This inflammasome was later shown to drive HCC in the DEN mouse model, where Aim2 ^−/− or Casp1 ^−/− mice had reduced carcinogenic liver injury and cancer growth (Martínez-Cardona et al., 2018). In the human skin, NLRP1 is the predominant inflammasome sensor. In 2016, Franklin et al. reported gain-of-function germline mutations in NLRP1 that lead to a familial skin inflammatory disease and associated carcinoma. The authors showed that inflammasome activation in keratinocytes leads to autocrine IL-1β that drives epidermal hyperplasia (Zhong et al., 2016).

Tumors use multiple means to evade anti-tumor immunity. For instance, they can usurp inflammatory pathways to establish an immunosuppressive environment. The inflammasome pathway is one such pathway demonstrated in some cancers to favor immunosuppression by promoting the genesis and recruitment of myeloid-derived suppressor cells (MDSC) or by inducing the differentiation of TAMs into a tolerogenic phenotype (Figure 2C). In 2010, using the poorly immunogenic B16-F10 melanoma model, van Deventer et al. showed that the Nlrp3 inflammasome suppressed the mouse response to dendritic cell tumor vaccines through MDSC recruitment (van Deventer et al., 2010). In a pancreatic ductal adenocarcinoma (PDAC) model, Daley et al. further implicated Nlrp3 signaling in TAM-mediated immunosuppression. They showed that deletion or inhibition of Nlrp3 inflammasome components was protective against PDAC. IL-1β mediated the tolerogenic function of Nlrp3 by regulating IL-10 production and T cell differentiation into Treg, Th2, and Th17 cells (Daley et al., 2017). Besides TAMs, PDAC tumor cells also activate the Nlrp3 inflammasome and act as a prominent source of IL-1β (Das et al., 2020). Tumor-derived IL-1β might also act via an IL-6-STAT3 inflammatory loop to expand MDSCs and induce immunosuppression (Tengesdal et al., 2021a). Tengesdal et al. have demonstrated this using the B16-F10 melanoma model and further showed that Nlrp3 inhibition with dapansutrile (OLT1177) abrogated the expression of immunosuppressives genes in PMN-MDSC and enhanced anti-tumor immunity in vivo (Tengesdal et al., 2021b). While NLRP3 appears to have a predominant role in dampening anti-tumor immunity, as illustrated above, other inflammasomes have also been implicated in this process. For instance, the NLRP1-IL-18 pathway was shown to promote the generation of mature MDSCs in multiple myeloma (Nakamura et al., 2018), and the Nlrc4 inflammasome in controlling CRC metastasis to the liver in non-alcoholic fatty liver disease (NAFLD) (Ohashi et al., 2019). Furthermore, the AIM2 inflammasome elicits immunosuppression following antibody-dependent cell phagocytosis (ADCP) and tumor cell DNA sensing, by upregulating PD-L1 and IDO expression, which inhibit anti-tumor immunity by NK and T cells (Su et al., 2018).

Notably, inflammasome-dependent cytokines such as IL-1β, can be produced in the TME independently of the inflammasomes. A recent work using mouse models of non-small cell lung cancer (NSCLC) and triple-negative breast cancer (TNBC) showed that IL-1β secretion by myeloid cells was independent of inflammasome activation and gasdermin D pore formation. IL-1β promoted immunosuppression by recruiting neutrophils to the tumor bed. The authors showed that tumor infiltration of neutrophils was abrogated in Il1b ^−/− mice, which resulted in loss of immunosuppression and restoration of anti-tumor immunity during treatment with antiangiogenic agents targeting VEGF. Although caspase-8 was activated in tumor-infiltrating myeloid cells, its deletion was not sufficient to completely block bioactive IL-1β release and neutrophil infiltration (Kiss et al., 2021). It is also worth noting that cytokine-independent functions of NLRP3 or AIM2 in immunosuppression have been documented. Petrilli and colleagues reported an immunosuppressive role of the Nlrp3-Asc-Caspase-1 pathway, that blunted NK cell tumor recruitment and activation, but that was independent of IL-1β, IL-18 or IL-1 receptor signaling. This was shown using orthotopic implantation of the breast cancer cell-line 4T1 in BALB/c mice or with MMTV-Neu^V664E on the BALB/c background crossed to C57Bl/6 inflammasome components-deficient mice (Guey et al., 2020). In addition, Theivanthiran et al. have shown that anti-PD1 immunotherapy leads to the upregulation of PD-L1 on tumor cell surface, which converges on NLRP3 activation and downstream release of heat shock protein (HSP) 70. In an autocrine and paracrine manner, HSP70 sensing by TLR4 and the subsequent expression and secretion of Wnt5a promoted the production of CXCL5 that attracts PMN-MDSCs to the tumor (Theivanthiran et al., 2021).

Inflammation is a protective biological response induced physiologically to counter pathogenic infection or tissue damage. Early studies by us and others have shown that the inflammasome pathway has a protective role in DSS-induced injury by promoting intestinal tissue repair via IL-18-mediated IEC regeneration (Dupaul-Chicoine et al., 2010). Concordantly, loss of Nlrp3, Asc or caspase-1 led to severe colitis but also to colitis-associated CRC (CAC) (Allen et al., 2010). Similarly, a role of Nlrp6 (Elinav et al., 2011), Nlrc4 (Rauch et al., 2017), Aim2 (Man et al., 2015) and pyrin (Sharma et al., 2018) inflammasomes in maintaining intestinal homeostasis and countering CAC was reported (Figure 3A). Flavell, Elinav and colleagues showed that this was mediated by alterations in the intestinal microbial ecology caused by lack of IL-18-instructed production of antimicrobial peptides (AMP) (Elinav et al., 2011; Levy et al., 2015). Such microbiota dysbiosis promoted neutrophil infiltration, chronic inflammation and IL-6 driven intestinal epithelial cell (IEC) hyper-proliferation (Hu et al., 2013). Besides controlling tissue homeostasis by triggering compensatory proliferation, inflammasome signalling counters tumorigenesis by upregulating differentiation programs. In the MMTV-PyMT mouse model, Castaño Z et al. have demonstrated an anti-metastatic role of IL-1β. They showed that myeloid-derived IL-1β imposed a differentiation “block” on metastasis-initiating cells (MICs) by upregulating ZEB1-dependent differentiation that countered their proliferative capacity (Castaño et al., 2018) (Figure 3A).

While in most instances, the underlying inflammasome mechanisms involve IL-18 or IL-1β, inflammasome-independent roles have also been described. For instance, Aim2 has been shown to restrict CAC and sporadic colon cancer through suppression of Akt signalling (Wilson et al., 2015) (Figure 3A). Inflammasome-independent functions were also reported for Nlrc4 in a subcutaneous B16-F10 melanoma mouse model. Nlrc4 expression in TAMs promoted a protective anti-tumoral response, contrary to caspase-1 or Asc, suggesting that Nlrc4 acted through an alternative mechanism (Janowski et al., 2016).

Tumor development depends on the balance between the capacity of the tumor to escape immunosurveillance and antitumor immune responses. The inflammasome-dependent cytokines IL-18 and IL-1β play a central role in anti-tumor immunity. In 2009, Ghiringhelli et al. have first reported that ATP release from tumor cells is sensed by the P2X7 receptor on dendritic cells (DC) which activate the Nlrp3 inflammasome, triggering the release of IL-1β. Deficiency in caspase-1 or IL-1r impaired the priming of INFγ-producing CD8⁺ T cells (Ghiringhelli et al., 2009) (Figure 3B). Consistently, IL-1β conditioning allows a better response of adoptively transferred anti-tumor T-cells. Mechanistically, IL-1β promotes T-cell homing to the tumor site and improves T cell survival and activation (Lee et al., 2019). As for IL-1β, IL-18 is an essential inducer of anti-tumor immunity. On one hand, it enhances NK cell maturation and FasL-mediated lytic activity, as demonstrated in a model of CRC metastasis to liver (Dupaul-Chicoine et al., 2015) (Figure 3B). On the other, IL-18 increases the numbers of tumor-infiltrating lymphocytes (TIL), as shown in subcutaneous model of melanoma (Zhou et al., 2020). However, IL-18 has previously failed to demonstrate efficacy in cancer clinical trials. A potential cause could be the expression of IL-18BP, a negative regulator that quenches circulating IL-18. Indeed, an IL-18 variant resistant to IL-18BP was shown to elicit increased TIL frequency and function, and to expand intra-tumoral stem-like TCF1⁺ CD8⁺ T cells in mouse tumors (Zhou et al., 2020). Akin to its role in natural anti-tumor immunity, the inflammasome also mediates synthetic anti-tumor immunity driven by certain immune checkpoint inhibitors and small molecule inhibitors of ectonucleotidases. For instance, CD39 inhibition which results in extracellular ATP accumulation enhanced anti-PD-1 anti-tumoral immune responses by engaging the P2x7-Nlrp3-IL-18 pathway (Xian-Yang Li et al., 2019; Yan et al., 2020) (Figure 3B). Similarly, unleashing Nlrp3 activity through the inhibition of Transmembrane protein 176B (TMEM176B), an immunoregulatory cation channel, enhanced TILs antitumor activity in response to immune checkpoint inhibitors (Segovia et al., 2019). More recently, Kuchroo and colleagues demonstrated that inhibition of the immune checkpoint TIM-3 on migratory DCs, resulted in strong anti-tumor immunity, mediated by ROS-driven Nlrp3 inflammasome activation (Dixon et al., 2021) (Figure 3B).

Pyroptosis is a lytic and immunogenic regulated cell death that is induced by caspase activation. The main mechanism of pyroptosis involves GSDMD processing into a pore forming domain. The GSDM family is well conserved in vertebrates and is composed of six paralogs in humans, GSDMA, GSDMB, GSDMC, GSDMD, GSDME (DFNA5) and GSDMF (DFNB59). Mice lack a GSDMB homolog, and have three GSDMDA homologs, four GSDMC homologs, GSDMD, GSDME, and GSDMF [reviewed in (Zou et al., 2021)]. Pyroptosis of tumor cells release a spectrum of molecules allowing an efficient anti-tumoral immune response and tumor regression. This was elegantly demonstrated in a biorthogonal system in mice, which revealed that pyroptosis of less than 15% of tumor cells was sufficient to clear the entire tumor graft. Such an anti-tumoral response is mediated by a competent immune system as immunodeficient mice or T-cell deficient mice were unable to induce anti-tumor immunity (Wang et al., 2020). In addition to GSDMD, GSDME can trigger pyroptosis. Its cleavage by caspase-3 downstream of TNF or chemotherapy drugs was shown to trigger pyroptosis (Wang et al., 2017). Tumor cells, but not normal cells, tend to downregulate GSDME, which partly explains the off-target toxicity of some cancer therapies (Figure 3C). Consistently, Gsdme ^−/− mice were protected from chemotherapy-induced tissue damage (Wang et al., 2017). In contrast to GSDME, GSDMC is upregulated in tumor cells. Through its interaction with Stat3, PD-L1 controls GSDMC transcription. TNF released by TAMs activates caspase-8, which processes GSDMC leading to pyroptosis (Hou et al., 2020).