Targeting inflammasomes as an immunotherapeutic strategy for cancer

Abstract

Inflammasomes are essential regulators of innate immunity, inflammation, and cellular apoptosis, and they have surfaced as significant modulators of cancer progression and regulation. Inflammasomes are macromolecular complexes assembled in response to damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs). They induce inflammation via the oligomerization and activation of caspases. These cysteine proteases cleave the pro-inflammatory cytokines IL-1β and IL-18 into their physiologically active mature versions. Recent discoveries reveal that inflammasomes are implicated not only in infections but also in malignancies, suggesting a significant connection between inflammation and tumor development. This article emphasizes that inflammasomes cause pyroptosis in a variety of immune cells, such as dendritic cells, macrophages, T cells, and fibroblasts, in addition to tumor cells. The induction of CD8⁺ T cells allows inflammasomes to commence an immunological response against the tumor, successfully inhibiting its growth and progression. The inflammasome comprises four main types: NLRP1, NLRP3, NLRC4, and AIM2. Nevertheless, the inflammasomes are activated by infection, injury, or stimulation of host cells, thus triggering the inflammatory response. The essential roles of the NLRP1, NLRP3, NLRC4, and AIM2 inflammasomes are emphasized in both tumors and immune cells. Furthermore, the article provides an overview of inhibitors targeting various tumor inflammasome pathways currently in clinical trials. Here, in this review, we underscore the role of the inflammatory response in cancer progression and highlight the significance of inflammasomes in regulating immune cells within the tumor microenvironment. Targeting these inflammasomes offers novel strategies for cancers.

Keywords: Immune cells; Immunotherapy; Inflammasome; Tumor microenvironment.

Fig. 1

Activation mechanism of canonical and non-canonical inflammasome. Canonical inflammasomes are triggered by pattern recognition receptors (NLRP3, NLRC4, AIM2) by the detection of PAMPs or DAMPs. A two-step signaling process is involved: priming signal (the expression of NLRP3 and IL-1β precursor induced by TLR ligands or TNF-α through the NF-κB pathway) and an activation phase (K + efflux and lysosomal degradation triggering NLRP3 oligomerization), followed by the recruitment of the adaptor protein ASC and the activation of caspase-1. Subsequently, IL-1β/IL-18 precursors and the GSDMD were cleaved to liberate mature inflammatory mediators and initiate pyroptosis. Non-canonical inflammasomes are directly activated through the recognition of intracellular LPS by caspase-4/5/11, independent of ASC, leading to pyroptosis via GSDMD cleavage, while also indirectly activating the classical NLRP3 pathway through K⁺ efflux or mitochondrial ROS, thereby creating a cascade that amplifies the inflammatory response. The green box signifies the non-canonical inflammasome

Fig. 2

The impact of inflammasome activation on immune cells and anti-tumor immunity. Pro-tumor: Chemotherapy triggers NLRP3-mediated pyroptosis in tumor cells, releasing ATP and DAMPs that recruit immunosuppressive CD39⁺ myeloid cells and M2 macrophages, driving tumor progression via IL-1β-induced EMT and MDSC recruitment. Anti-tumor: NLRP3/AIM2 activation induces pyroptosis and IL-18 release, enhancing NK/CD8⁺ T cell cytotoxicity (via IFN-γ/PD-L1 suppression) and polarizing M1 macrophages to secrete IL-12 for Th1 activation. Spatial segregation and color-coding (red arrows: pro-tumor; black arrows: anti-tumor)

Fig. 3

Inhibitors of various tumor inflammasomes in the clinical trials. Red arrows: The inflammasome pathway promotes cancer; black arrows: inflammasome inhibitor drugs have been reported to treat these cancers