Fig. 2

Major factors operating in the establishment of immunoresistant milieu and actionable combinations with ICBs: Yin and Yang effects. Many potential tumor, host, and environmental-related factors might explain the degree of heterogeneity seen with ICB therapy, dividing into influences from the TME, endocrine and metabolic factors, environmental factors, and other influences, i.e., age and unfavorable host genetics (Yin). Each step the cancer-immunity cycle requires the coordination of numerous factors, both stimulatory, promoting immunity and inhibitory, helping keep the process in check and reducing immune activity and/or preventing autoimmunity in nature. The numerous factors that come into play in the cancer-immunity cycle provide a wide range of potential therapeutic targets, highlighting examples of some of the therapies currently under pre-clinical or clinical evaluation. Key highlights include that vaccines can primarily promote cancer antigen presentation, anti-CTLA-4 can primarily promote priming and activation, and anti-PD-L1 or anti-PD-1 antibodies can primarily promote killing of cancer cells. Although not developed as immunotherapies, chemotherapy, radiation therapy, and targeted therapies can primarily promote release of tumor cell antigens, and inhibitors of VEGF can potentially promote T cell infiltration into tumors (Yang)