Synergistic cell death pathways in gastrointestinal tumor immunotherapy: molecular mechanisms, metabolic reprogramming, and clinical translation

This review elucidates the intricate interplay between regulated cell death pathways—autophagy, ferroptosis, and cuproptosis—and their synergistic potential for immunotherapy in gastrointestinal tumors. By systematically dissecting the molecular mechanisms of these pathways, the authors highlight their dynamic regulation of the tumor immune microenvironment, including antigen presentation, metabolic competition, and immune evasion. Key insights include autophagy-mediated programmed death ligand-1 degradation, ferroptosis-driven immunogenic feedback via lipid peroxidation, and cuproptosis-induced mitochondrial collapse through copper-dependent proteotoxic stress. The review critically evaluates emerging combination strategies, such as autophagy inhibitors with immune checkpoint inhibitors, iron/copper-targeted nanomedicines coupled with photothermal therapy, and metabolic reprogramming interventions. These approaches demonstrate enhanced efficacy in overcoming drug resistance and reversing the immunosuppressive features of the tumor immune microenvironment. Despite promising preclinical advances, challenges such as tumor heterogeneity, spatiotemporal regulation of cell death–immune crosstalk, and clinical translation barriers are underscored. The authors advocate for multidisciplinary integration of nanotechnology, artificial intelligence, and multi-omics to optimize precision therapies. This work provides a robust framework for leveraging regulated cell death pathways to refine immunotherapy paradigms in gastrointestinal tumors, from mechanistic discoveries to actionable clinical strategies.