Intrinsic and acquired cancer immunotherapy resistance

Abstract Cancer immunotherapies, such as immune checkpoint inhibitors (ICIs), have revolutionized the treatment of various cancers and have shown a great efficacy in inducing antitumor immunity. Cancer immunotherapy in the form of adoptive cell transfer (ACT) have also been developed to eradicate tumor cells in a specific and effective manner, and it includes the administration of autologous tumor-infiltrating T-cells (TILs), T-cell receptor (TCR)-modified T-cells, or genetically engineered chimeric antigen receptor (CAR)-specific T-cells (CARTs) in cancer patients. Additionally, cancer vaccines and recombinant cytokines can be used as monotherapy or adjuvant therapy. Despite the success of immunotherapies in treating various solid tumors and hematologic malignancies, a significant number of patients do not benefit from these therapies and exhibit limited or no response. Some cancer patients do not respond to immunotherapies as a result of primary or intrinsic tumor resistance, while others respond to immunotherapies but develop resistance over time, referred to as adaptive or acquired tumor resistance. Tumor intrinsic- and extrinsic-mediated mechanisms, including genetic and epigenetic alterations, tumor-mutational loads, overexpression of co-inhibitory immune checkpoints, and elevated levels of suppressive immune cells and cytokines, can lead to a compromised antitumor immunity favoring tumorigenesis and cancer progression. This chapter outlines mechanisms of intrinsic tumor resistance and the emergence of acquired tumor resistance to cancer immunotherapies. Moreover, this chapter describes combined cancer immunotherapies, which may offer a great therapeutic potential to overcome tumor resistance against therapy and improve clinical outcomes in cancer patients.