Manipulation of tumor microenvironment by induction of immunogenic cell death and immune check point inhibitors for enhancing the efficacy of cancer treatments

The immunosuppressive tumor microenvironment (TME) is a major obstacle to the effectiveness of cancer therapies. This article reviews the combination of immunotherapy, particularly immune checkpoint inhibitory antibodies (mAbs), with radiotherapy (RT) and chemotherapy (CT) as a strategy to enhance anti-tumor efficacy of cancer treatments in human malignancies that are resistant to treatment. Immunogenic cell death (ICD) induced by RT and certain CTs, releases damage-associated molecular patterns (DAMPs), activating antigen-presenting cells (APCs) in particular dendritic cells (DCs). DCs within immunosuppressive TME mostly get immunosuppressed and become tolerogenic leading to the induction of cancer tolerance. Generation of DAMPs in TME can restore the function of tolerogenic DCs leading to their functional maturation. Activated DCs can initiate anticancer immune responses by activating the proliferation of cytotoxic T lymphocytes (CTLs) and promoting the function of natural killer (NK) cells. Combination of DAMPs inducers with immune checkpoint inhibitory mAbs, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 antibodies, can effectively enhance DCs and CTL activity within the TME. Clinical evidence demonstrates improved therapeutic outcomes in the patients who have received combination therapies included with immune checkpoint inhibitors and DAMP inducers. This approach of combining ICD-inducing agents with immune checkpoint inhibitory mAbs optimizes immune activation by shifting the TME from immunosuppressive to immune-supportive, thus enhancing anti-tumor immunity. Future research should focus on optimizing dosing, regimens, identifying predictive biomarkers, and refining patient selection criteria to maximize treatment efficacy and personalize cancer therapy. Integrating mAb-based immunotherapy with RT and CT represents a transformative approach in oncology, with a potential to turn certain cancers into manageable chronic diseases. "Synergistic Integration of Conventional and Emerging ICD-Inducers with Immune Checkpoint Blockade to Remodel the TME" This graphical abstract illustrates the strategic conversion of a "cold" immunosuppressive tumor microenvironment (TME) into a "hot" immunologically active environment through multimodal interventions. •(Left) Multimodal Induction of ICD: Beyond conventional treatments (Radiotherapy (RT) and Chemotherapy (CT)), emerging non-conventional strategies—including Ferroptosis-inducers and Photo/Sonodynamic Therapy (PDT/SDT)—alongside nanoparticle-mediated delivery systems (NPs), are utilized to trigger robust Immunogenic Cell Death (ICD) in resistant cancer cells. •(Center) Molecular Mechanisms: This process leads to the spatiotemporal release of Damage-Associated Molecular Patterns (DAMPs) and the translocation of mitochondrial DNA (mtDNA), which subsequently activates the cGAS-STING pathway, driving Type I interferon production and pro-inflammatory signaling. •(Right) Therapeutic Outcome: The resulting maturation of dendritic cells (DCs) and efficient priming of cytotoxic T lymphocytes (CTLs), synergized with dual immune checkpoint blockade (targeting PD-1 and CTLA-4), effectively overcomes TME barriers. This integrated approach leads to potent anti-tumor immunity and enhanced therapeutic outcomes in treatment-resistant human malignancies. • ICD inducers remodel the TME to enhance cancer immunotherapy efficacy. • Emerging Ferroptosis and PDT/SDT therapies act as potent ICD inducers. • Combination of ICIs with RT/CT overcomes resistance in malignancies. • DAMPs and the cGAS-STING pathway are vital for 'cold' tumor conversion. • Dual PD-1/CTLA-4 blockade synergizes with ICD for improved outcomes.