The NLRP3 inflammasome in gastrointestinal malignancies: molecular mechanisms, regulatory networks, and therapeutic opportunities.

backgroundThe NLRP3 inflammasome is a key inflammatory sensing platform in the innate immune system. It integrates pathogen-associated molecular patterns, damage-associated molecular patterns, and diverse cellular stress signals. Once activated, it promotes caspase-1 activation, maturation and release of IL-1β and IL-18, and gasdermin D-mediated pyroptosis. Through these processes, the NLRP3 inflammasome contributes to inflammatory responses and the maintenance of tissue homeostasis. Increasing evidence has shown that the NLRP3 inflammasome plays a critical but complex role in the initiation and progression of gastrointestinal malignancies. MAIN BODY: In esophageal cancer, gastric cancer, and colorectal cancer, NLRP3 activity can be regulated by microbial infection, bile acid stimulation, environmental carcinogens, gut dysbiosis, metabolic abnormalities, mitochondrial dysfunction, reactive oxygen species accumulation, and treatment-induced stress. Sustained or aberrant NLRP3 activation may promote chronic inflammation, epithelial barrier disruption, IL-1β-mediated myeloid cell recruitment, immunosuppressive microenvironment formation, tumor invasion and metastasis, and therapeutic resistance. In contrast, under specific therapeutic conditions, NLRP3-mediated pyroptosis in tumor cells can enhance antigen release, activate antitumor immunity, and improve the efficacy of chemotherapy, radiotherapy, and immune checkpoint inhibitors. Therefore, the function of the NLRP3 inflammasome in gastrointestinal tumors is highly dependent on cell type, disease stage, inflammatory intensity, immune composition, and treatment context. This review summarizes the molecular mechanisms of NLRP3 inflammasome activation, its tumor-promoting and tumor-suppressive roles in gastrointestinal malignancies, its relationship with immune checkpoint inhibitor response, and emerging therapeutic strategies targeting this pathway.

conclusionsThe NLRP3 inflammasome is not simply a tumor-promoting or tumor-suppressive factor in gastrointestinal malignancies. Instead, its biological effects are highly context dependent. Precise modulation of NLRP3, rather than simple inhibition or activation, may provide new opportunities for individualized treatment of gastrointestinal cancers. Future studies should define the cellular source, activation state, downstream effector profile, and immune context of NLRP3 signaling to guide rational therapeutic application.