Subsets of human tumors are infiltrated with tumor antigen–specific CD8⁺ T cells [tumor-infiltrating lymphocytes (TILs)] despite tumor progression. These TILs are thought to be inactivated by the immunosuppressive tumor microenvironment, through the engagement of inhibitory receptors such as CTLA-4 and PD-1. However, antigen-specific CD8⁺ TILs are not functionally inert but are undergoing activation in situ. Here, we show that antigen-specific CD8⁺ TILs are actively proliferating, yet also undergo high rates of apoptosis, leading to a vicious cycle of activation and death that limits immune efficacy. Preventing CD8⁺ TIL apoptosis by Bcl-x_L overexpression enabled accumulation and improved tumor control. Effective combination immunotherapy with an agonist 4-1BB mAb plus either CTLA-4 or PD-L1 neutralization led to a marked accumulation of specific CD8⁺ TILs through decreased apoptosis rather than increased T-cell entry or proliferation. Our data suggest that antigen-driven apoptosis of CD8⁺ TILs is a barrier to effective spontaneous antitumor immunity and should be considered as a critical factor in the development of cancer immunotherapies. Cancer Immunol Res; 6(1); 14–24. ©2017 AACR.