Immunogenic Cell Death as a Target for Combination Therapies in Solid Tumors: A Systematic Review Toward a New Paradigm in Immuno-Oncology

Abstract

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.

Keywords: combination therapy; immune checkpoint inhibition; immunogenic cell death; oncolytic virotherapy; photodynamic therapy; radiotherapy; solid tumors.

Figure 1. PRISMA 2020 flowchart.

Flow diagram illustrating the selection process of studies included in the systematic review, based on PRISMA 2020 guidelines. A total of 1,187 records were identified, 1,041 were screened, and 14 studies met the eligibility criteria and were included in the final synthesis. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses

Figure 2. Conceptual model of mechanistic convergence and therapeutic integration for ICD-based strategies in solid tumors.

This diagram illustrates how diverse treatment modalities, such as radiotherapy, chemotherapy, PDT, and oncolytic virotherapy, converge on shared cellular stress pathways that promote ICD. Key stress responses include ER stress, ROS generation, lysosomal destabilization, and STING/IFN-I signaling. These trigger the release of DAMPs such as CRT, ATP, and HMGB1, which facilitate dendritic cell maturation and antigen cross-presentation. Combination with immune checkpoint inhibitors (e.g., anti-PD-1, anti-CTLA-4) enhances effector T-cell responses and long-term antitumor immunity. This integrative framework supports the rational design of combination regimens targeting ICD as a central node in cancer immunotherapy. Image created by the authors. No external sources used. No permission required. ICD, immunogenic cell death; PDT, photodynamic therapy; ER, endoplasmic reticulum; ROS, reactive oxygen species; STING, stimulator of interferon genes; IFN-I, type I interferon; DAMPs, damage-associated molecular patterns; CRT, calreticulin; ATP, adenosine triphosphate; HMGB1, high-mobility group box 1; DC, dendritic cell; PD-1, programmed cell death protein 1; CTLA-4, cytotoxic T lymphocyte-associated antigen 4