Immunogenic Cell Death as a Target for Combination Therapies in Solid Tumors: A Systematic Review Toward a New...

Immunogenic cell death (ICD) represents a distinct form of regulated cell death that triggers robust antitumor immune responses through the release of damage-associated molecular patterns (DAMPs) such as calreticulin (CRT), extracellular adenosine triphosphate (ATP), and high-mobility group box 1 protein (HMGB1). While ICD has emerged as a promising strategy to enhance cancer immunotherapy, its integration into therapeutic regimens remains fragmented. This systematic review aimed to synthesize the experimental evidence on ICD-inducing treatments in solid tumors and assess the convergence of mechanistic pathways and combination strategies. A comprehensive literature search identified 14 eligible studies published between 2010 and 2025, including preclinical in vitro and in vivo investigations of radiotherapy, chemotherapy, photodynamic therapy (PDT), oncolytic virotherapy, and redox- or lysosome-targeted agents. Despite mechanistic diversity, most interventions converged on shared cellular stress responses, notably endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) production, leading to DAMP exposure and dendritic cell maturation. Eight studies incorporated immune checkpoint inhibitors, revealing synergistic antitumor effects and immune memory enhancement. While most studies demonstrated in vivo efficacy, two relied solely on in vitro or ex vivo models. The risk of bias was low in the majority of cases. Collectively, the evidence supports ICD as a central immunologic interface capable of transforming cytotoxic therapies into immune-activating treatments. Future clinical research should prioritize ICD biomarker validation, optimization of treatment timing, and development of personalized ICD-based combination regimens. These findings reinforce the potential of ICD to serve as a unifying framework in the next generation of cancer immunotherapies.