Immunogenic cell death as a cornerstone for combination therapies with immune checkpoint blockade

Immune checkpoint blockade (ICB) has significantly advanced tumor therapy, yet its overall response rates remain limited and are often accompanied by immune-related adverse effects. Immunogenic cell death (ICD), a specialized form of regulated cell death, elicits antitumor immunity through the release of damage-associated molecular patterns and cytokines. This review systematically examines the mechanisms by which ICD enhances the efficacy of ICB therapy and evaluates its potential for clinical translation. ICD facilitates the recruitment of dendritic cells into the tumor microenvironment via “find me” signals and, through the exposure of “eat me” signals, enables dendritic cell-mediated phagocytosis and antigen presentation of tumor cells. This cascade effectively transforms immunologically “cold” tumors into “hot” tumors, augmenting cytotoxic T lymphocyte infiltration and function, thereby improving ICB therapeutic outcomes. Additionally, ICD promotes the formation of tertiary lymphoid structures, which further remodel the tumor microenvironment and support sustained immune surveillance. Although preclinical studies underscore the synergistic potential of combining ICD inducers with ICB, clinical trial outcomes have been variable, with efficacy influenced by tumor heterogeneity, treatment sequencing, and the immunosuppressive tumor microenvironment. Future investigations should focus on optimizing ICD induction protocols, developing specific biomarkers, and designing personalized combination strategies to enable more precise and effective immunotherapeutic interventions in oncology.