Mechanisms of CD8+ T cell exclusion and dysfunction in cancer resistance to anti-PD-(L)1

CD8⁺ T cells are the front-line defensive cells against cancer. Reduced infiltration and effector function of CD8⁺ T cells occurs in cancer and is contributed to defective immunity and immunotherapy resistance. Exclusion and exhaustion of CD8⁺ T cells are the two key factors associated with reduced durability of immune checkpoint inhibitor (ICI) therapy. Initially activated T cells upon exposure to chronic antigen stimulation or immunosuppressive tumor microenvironment (TME) acquire a hyporesponsive state that progressively lose their effector function. Thus, a key strategy in cancer immunotherapy is to look for factors contributed to defective CD8⁺ T cell infiltration and function. Targeting such factors can define a promising supplementary approach in patients receiving anti-programmed death-1 receptor (PD-1)/anti-programmed death-ligand 1 (PD-L1) therapy. Recently, bispecific antibodies are developed against PD-(L)1 and a dominant factor within TME, representing higher safety profile and exerting more desired outcomes. The focus of this review is to discuss about promoters of deficient infiltration and effector function of CD8⁺ T cells and their addressing in cancer ICI therapy.