Therapeutic targeting of trained immunity in cancer

Cancer immunotherapy has transformed the treatment of several malignancies. Yet, its therapeutic efficiency remains ineffective due to the diversity and immune-resistance of the tumor microenvironment (TME). Trained immunity is the capability of innate immune cells to acquire immunological memory upon exposure to specific stimuli, followed by metabolic and epigenetic reprogramming, and offers an emerging strategy against cancers. In various forms of cancer, trained immunity (TI) leads to enhance the cytokine release, reactive oxygen species (ROS) production, phagocytosis, antigen presentation, and modification of the tumor microenvironment, which may have antitumor effects, depending on the tumor type. Mechanistically, the trained immunity is supported by mTOR/HIF1α-mediated aerobic glycolysis, histone modifications of proinflammatory genes, and reprogramming of hematopoietic stem cells and progenitor cells (HSPCs) in the bone marrow, thus driving the central, peripheral, and effector arms of anti-tumor immunity, simultaneously. This review discusses the mechanisms of trained immunity in cancer therapy and evaluates the current therapeutic approaches.