Programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1)-blockade immunotherapies have limited efficacy in the treatment of bladder cancer. Here, we show that NKG2A associates with improved survival and responsiveness to PD-L1 blockade immunotherapy in bladder tumors that have high abundance of CD8+ T cells. In bladder tumors, NKG2A is acquired on CD8+ T cells later than PD-1 as well as other well-established immune checkpoints. NKG2A+ PD-1+ CD8+ T cells diverge from classically defined exhausted T cells through their ability to react to human leukocyte antigen (HLA) class I-deficient tumors using T cell receptor (TCR)-independent innate-like mechanisms. HLA-ABC expression by bladder tumors is progressively diminished as disease progresses, framing the importance of targeting TCR-independent anti-tumor functions. Notably, NKG2A+ CD8+ T cells are inhibited when HLA-E is expressed by tumors and partly restored upon NKG2A blockade in an HLA-E-dependent manner. Overall, our study provides a framework for subsequent clinical trials combining NKG2A blockade with other T cell-targeted immunotherapies, where tumors express higher levels of HLA-E. [Display omitted] • NKG2A associates with better survival and response to anti-PD-L1 in bladder cancer • NKG2A is upregulated after PD-1 is acquired on tumor-infiltrated CD8+ T cells • NKG2A+ CD8+ T cells react to HLA-ABC-deficient tumors with innate-like function • NKG2A blockade enhances TCR-independent cytotoxicity by CD8+ T cells Salomé et al. characterize the role of the NKG2A/HLA-E immune checkpoint axis in bladder cancer. Tumor escape mechanisms include loss of HLA-ABC expression. NKG2A+ CD8+ T cells react to advanced HLA-ABC-deficient tumors through acquired TCR-independent cytotoxicity mechanisms. NKG2A blockade further enhances their innate-like functions in the presence of HLA-E. [ABSTRACT FROM AUTHOR]