Collectively, our study showed that BTLA and PD-1 cooperatively inhibit the activity of CD8+ T cells and are associated with resistance to PD-1/PD-L1 pathway blockade in NSCLC patients and that anti-BTLA blockade enhances the antitumor efficacy of anti-PD-L1 blockade by reversing the exhausted phenotype of BTLA+PD-1+CD8+ T cells, which suggests that dual BTLA and PD-1/PD-L1 blockade should be further explored to elicit potent antitumor CD8+ T-cell responses in NSCLC patients. Here, CD8A is linked to non-small cell lung carcinoma.