Single-Cell Pan-Cancer Atlas Reveals GPR171 as a Candidate Marker of CD8+ T-Cell Dysfunction

CD8+ T-cell exhaustion is a key mechanism of tumor immune evasion and a major limitation of current cancer immunotherapy. However, the molecular factors sustaining dysfunctional CD8+ T-cell states across cancers are not fully understood. Here, we identify GPR171 as a common feature of exhausted CD8+ T cells across multiple solid tumors based on integrated pan-cancer single-cell transcriptomic analyses. GPR171 is enriched in exhausted CD8+ T cells and is closely associated with immunosuppressive and exhaustion-related gene programs. It also shows a strong association with key immune regulatory genes such as CTLA4 and NR4A2. Functional analyses suggest that reduced GPR171 activity is associated with decreased expression of exhaustion-related genes and a shift toward cytotoxic and immune-activating programs. In parallel, a CREM-centered regulatory network emerges in exhausted CD8+ T cells and may act in concert with GPR171-associated programs to reinforce dysfunctional states. Overall, our results identify GPR171 as a candidate marker of CD8+ T-cell dysfunction across cancers and provide a systematic pan-cancer single-cell characterization of its association with immunosuppressive T-cell states, supporting its potential as a therapeutic target for restoring antitumor immunity.