Cracking the code of cancer immunotherapy resistance: emerging roles of pyroptosis and necroptosis

Therapeutic resistance and recurrent metastasis continue to pose major obstacles in the treatment of malignant tumors worldwide. Immunogenic cell death (ICD), characterized by its ability to both eliminate cancer cells and stimulate antitumor immune responses, has emerged as a promising strategy in the field of cancer immunotherapy. As key subtypes of ICD, pyroptosis and necroptosis contribute significantly to remodeling the tumor microenvironment (TME) and modulating immune responses through their distinct death-immunity coupling mechanisms. Characterized by plasma membrane pore formation and subsequent release of cytoplasmic contents, pyroptosis and necroptosis reprogram the immune microenvironment, thereby laying the groundwork for enhanced antitumor immune responses. Paradoxically, the chronic activation of pyroptosis and necroptosis pathways may contribute to cancer progression. Sustained inflammation within the TME promotes the release of pro-angiogenic and immunosuppressive factors, driving myeloid-derived suppressor cells (MDSCs) recruitment, extracellular matrix remodeling, and metastatic niche formation, thereby facilitating tumorigenesis and metastasis. The context-dependent dual roles of pyroptosis and necroptosis—shaped by tumor histotype, chronic inflammation, and stromal context—highlight the need for a nuanced understanding of their tumor-specific functions across cancer types. This review outlines the underlying mechanisms of pyroptosis and necroptosis, and summarizes recent advances, aiming to inform and inspire novel strategies in overcoming cancer immunotherapy resistance.