Microbial reprogramming of immunogenic cell death: a new paradigm in tumor immunotherapy

Immunogenic cell death (ICD), a special form of cell death, transforms “cold” tumors into “hot” tumors by fulfilling the following three key conditions: antigenicity; adjuvanticity; and a suitable tumor microenvironment (TME). Tumor cells release damage-associated molecular patterns (DAMPs) during ICD, thereby activating the dendritic–cytotoxic T cell axis to elicit systemic antitumor immune responses. However, drug resistance and immune-related adverse effects often limit traditional ICD inducers, including chemotherapy and radiotherapy. Notably, microbiota and microbial metabolites can trigger ICD in tumor cells, leading to the release of DAMPs, modulation of immune cell functions, and TME remodeling. This study comprehensively reviews the mechanisms underlying ICD regulation via microbiota and microbial metabolites. In addition, this review examines emerging strategies, including engineered microbiota, microbial-based combination therapies (such as incorporating immune checkpoint inhibitors or chemotherapy), and dietary interventions. Despite challenges associated with individual microbiota variability and mechanistic complexity, this study highlights the potential of microbiota-mediated ICD modulation as a novel paradigm for personalized cancer therapy, thereby providing insights for future directions of scientific research.