The immune system has the potential to recognize and eliminate tumor cells, and failed immune surveillance contributes to cancer development. Many immunotherapeutics, including checkpoint blockade therapy, harness the endogenous antitumor immune response. While clinical benefit can be profound in some cases, some patients show primary resistance, whereas others experience clinical response and then develop secondary resistance under immune selective pressure. In this review, we discuss tumor cell–intrinsic mechanisms of primary and secondary immune evasion, both of which contribute to resistance to immunotherapeutic interventions. General mechanisms include adaptive evasion, allowing the tumor to establish equilibrium with an existing T cell infiltrate, and innate evasion, in which T cells and other immune cells are excluded from the tumor microenvironment. Evidence suggests that both processes can mediate resistance to checkpoint blockade therapy, but the different biological processes involved may necessitate distinct treatment strategies for overcoming resistance therapeutically.


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