Molecular mechanisms and functions of pyroptosis in inflammation and antitumor immunity

Abstract

Canonically, gasdermin D (GSDMD) cleavage by caspase-1 through inflammasome signaling triggers immune cell pyroptosis (ICP) as a host defense against pathogen infection. However, cancer cell pyroptosis (CCP) was recently discovered to be activated by distinct molecular mechanisms in which GSDMB, GSDMC, and GSDME, rather than GSDMD, are the executioners. Moreover, instead of inflammatory caspases, apoptotic caspases and granzymes are required for gasdermin protein cleavage to induce CCP. Sufficient accumulation of protease-cleaved gasdermin proteins is the prerequisite for CCP. Inflammation induced by ICP or CCP results in diametrically opposite effects on antitumor immunity because of the differential duration and released cellular contents, leading to contrary effects on therapeutic outcomes. Here, we focus on the distinct mechanisms of ICP and CCP and discuss the roles of ICP and CCP in inflammation and antitumor immunity, representing actionable targets.

Keywords: Antitumor immunity; Cancer cell pyroptosis; Gasdermin; Immune cell pyroptosis; Inflammation; Pyroptosis.

Figure 1.. Pyroptotic pathway in immune cells.

Canonically, pathogens drive inflammasome formation in macrophages to activate caspase-1 which subsequently cleaves GSDMD and promotes IL-1β/IL-18 maturation. GSDMD-N terminal domain oligomerizes and forms pores in cell membrane, leading to cell lysis and IL-1β/IL-18 release. However, gram-negative bacteria-derived lipopolysaccharide (LPS) is able to directly activate caspase-11 to cleave GSDMD and form GSDMD pores. Potassium efflux though GSDMD pores then triggers canonical inflammasome-induced pyroptotic pathway. Activated caspase-8 by TNFα signaling or Yersinia-derived YopJ-induced TAK1 inhibition has also been shown to cleave GSDMD to cause cell lysis, which could be negatively regulated by cFLIPL. GSDMD succination by fumarate prevents its cleavage by caspases, limiting its capacity of pyroptosis induction. Mg²⁺ blocks pyroptosis by inhibiting Ca²⁺ channel P2X7 which is required for GSDMD pore formation. Pyroptotic process could be reversed by ESCRT-III machinery-dependent plasma membrane repair.

Figure 2.. Diverse, cell-context dependent impacts of ICP-released IL-1β and IL-18 on tumor cells and tumor immune microenvironment.

IL-1β and IL-18 are the products of ICP, through which anti-tumor immunity and tumor growth are affected in a cell context-dependent manner. IL-1β promotes VEGFA expression and angiogenesis, and thus attracts MDSC into tumor microenvironment. It is well-known for its enhancement in tumor progression, oncogenesis, lymphangiogenesis, and metastasis and suppression in antitumor effect of chemotherapy drugs. Instead, the role of IL-18 in tumor prevention and suppression is impressive. It increases IFN-γ production of Th1 cells, boosts antitumor activity of macrophage, and fuels the cytotoxicity of killer lymphocytes. It protects intestine from damage, preventing intestine inflammation. Administration of IL-18 reduces tumor incidence and kills tumor cells in metastasis sites, leading to inhibition of tumor progression.

Figure 3.. CCP-induced acute inflammation enhances, however, ICP-mediated chronic inflammation inhibits anti-tumor immunity.

Killer lymphocytes including NK cells and T cells induce apoptosis or ferroptosis in gasdermin-negative cancer cells but trigger pyroptosis of cancer cells expressing GSDME and GSDMB (CCP), which promotes acute (short-term) inflammation and enhances killer lymphocytes cytotoxicity, leading to tumor growth suppression. Instead, pyroptosis of immune cells (ICP) including TAM and MDSC causes chronic (long-term) inflammation that inhibits killer cells activity and fuels tumor growth. The difference of inflammation duration between ICP and CCP causes distinct outcomes in tumor growth.