Immune checkpoint blockade (ICB) targeting PD-1 and CTLA-4 has revolutionized cancer treatment. However, many cancers do not respond to ICB, prompting the search for additional strategies to achieve durable responses. G-protein-coupled receptors (GPCRs) are the most intensively studied drug targets but are underexplored in immuno-oncology. Here, we cross-integrated large singe-cell RNA-sequencing datasets from CD8⁺ T cells covering 19 distinct cancer types and identified an enrichment of Gα_s-coupled GPCRs on exhausted CD8⁺ T cells. These include EP₂, EP₄, A_2AR, β₁AR and β₂AR, all of which promote T cell dysfunction. We also developed transgenic mice expressing a chemogenetic CD8-restricted Gα_s-DREADD to activate CD8-restricted Gα_s signaling and show that a Gα_s-PKA signaling axis promotes CD8⁺ T cell dysfunction and immunotherapy failure. These data indicate that Gα_s-GPCRs are druggable immune checkpoints that might be targeted to enhance the response to ICB immunotherapies.