The genetic and epigenetic aberrations that underlie immune resistance lead to tumors that are refractory to clinically established and experimental immunotherapies, including monoclonal antibodies and T cell-based therapies. From various forms of cytotoxic T cells to small molecule inhibitors that revamp the tumor microenvironment, these therapies have demonstrated notable responses in cancer models and a resistant subset of cancer patients, used both alone and in combination. However, even current approaches, such as those targeting checkpoint molecules, tumor ligands, and involving gene-related therapies, present a challenge in non-responding patients. In this perspective, we discuss the most common mechanisms of immune resistance, including tumor heterogeneity, tumor ligand and major histocompatibility complex modulation, anti-apoptotic pathways, checkpoint inhibitory ligands, immunosuppressive cells and factors in the tumor microenvironment, and activation-induced cell death. In addition, we discuss the strategies designed to circumvent these resistance pathways to showcase the potential of emerging technologies in battling the rise of resistance.
Keywords: Immune system; T cells; cancer; checkpoint inhibitors; heterogeneity; immune resistance; survival pathways; tumor microenvironment.