Immune checkpoint blockade therapy (ICBT), which blocks negative immune-activating signals and maintains the antitumor response, has elicited a remarkable clinical response in certain cancer patients. However, intrinsic resistance (i.e., insensitivity of the tumors to therapy) remains a daunting challenge. The efficacy of ICBT is tightly modulated by the function of each step in the antitumor immunity cycle. Mechanistically, the number of mutations determines tumor immunogenicity. The properties of the tumor microenvironment control T-cell infiltration, distribution, and function in tumor tissues. Low tumor immunogenicity and a strong immunosuppressive tumor microenvironment cause significant intrinsic resistance to ICBT. With our evolving understanding of intrinsic resistance, people have successfully tested, in preclinical models, treatments targeting specific resistance mechanisms to sensitize ICBT-resistant tumors. Translation of those preclinical findings to the clinical arena will help generate personalized ICBT strategies that target tumorspecific resistance mechanisms. Progress in the new personalized ICBT strategies will expand the reach of immunotherapy to more cancer types, thus enabling more patients to benefit.
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We thank Drs. Lihua Li and Anne Sarver for helpful discussions and Leeanne Dongses and Dr. Mary Knatterud for assisting in manuscript preparation. Because of space restrictions, we cannot cite many other significant contributions made by numerous researchers and laboratories in this potentially important and rapidly progressing field. S. Subramanian was supported by research grants funded by the American Cancer Society (grant RSG 13-381-01-RMC), the Zach Sobiech Osteosarcoma Fund, and the Karen Wyckoff Rein in Sarcoma Foundation. X. Zhao was supported by a University of Minnesota Department of Surgery research fellowship.