Multifaceted roles of the NLRC4 inflammasome in cancer: from molecular mechanisms to therapeutic implications

• NLRC4 forms an inflammasome complex that controls the development and progression of infection, autoinflammation and cancer. • NLRC4 triggers protective or pathological inflammasome responses and inflammation, reflecting its tumor-attenuating and tumor-promoting roles. • NLRC4 forms novel tumor-attenuating complexes independently of inflammasomes that activate DNA damage responses. • NLRC4 may serve as a biomarker in the prognosis and treatment response for certain cancers. NLRC4 forms an inflammasome complex and activates a critical innate immune response to bacterial infection. The NLRC4 inflammasome triggers the activation of the cysteine protease caspase-1, leading to the proteolytic maturation of the pro-inflammatory cytokines IL-1β and IL-18, and the induction of pyroptosis. The role of NLRC4 in antimicrobial defense is well-established, but emerging evidence highlights a complex and often paradoxical functions of NLRC4 in the development and progression of cancer. NLRC4 acts as a tumor suppressor in colorectal and intestinal cancer, and potentially melanoma. NLRC4 also forms unique tumor-attenuating protein complexes, independently of NAIPs, ASC and caspase-1, that activate the DNA damage response. In obesity-associated cancers and metastasis, NLRC4 is pro-tumorigenic and promotes pathological inflammation and angiogenesis. Understanding the precise regulatory mechanisms of NLRC4 in cancer will provide insights into the development of personalized immunotherapies. This review discusses the multi-functional roles of NLRC4 in cancer and explores the potential clinical utility of targeting NLRC4 in therapies.