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.