PD‐L1 on Tumor‐Derived Extracellular Vesicles Induces CD8 ⁺ T Cell Terminal Exhaustion and Mediates Anti‐PD‐1 Resistance in Head and Neck Squamous Cell Carcinoma

Head and neck squamous cell carcinoma (HNSCC) demonstrates suboptimal responses to current immune checkpoint inhibitors (ICIs), with objective response rates (ORRs) of merely 15-20%. The molecular mechanisms underlying these low ORRs remain incompletely defined. Here, two functionally distinct CD8⁺ T cell subsets are identified within the tumor microenvironment: precursor exhausted T (Tex^prog) cells and terminally exhausted T (Tex^term) cells. Notably, although anti-PD-1 therapy reduced Tex^prog cell frequencies, it failed to reverse Tex^term cells. Elevated Tex^term cell infiltration correlated with advanced tumor-node-metastasis (TNM) staging and poor prognosis. Furthermore, non-responders exhibited significantly higher baseline Tex^term proportions than responders before immunotherapy. Multivariate analysis established stromal Tex^term cell density as both an independent prognostic factor and predictor of ICIs resistance. Mechanistically, Tex^term cell infiltration strongly correlated with PD-L1 on tumor-derived extracellular vesicles (PD-L1⁺EVs). Most importantly, it is demonstrated that PD-L1⁺EVs drive Tex^term cell differentiation by upregulating the basic leucine zipper transcription factor, ATF-like (BATF) in CD8⁺ T cells. Knocking out PD-L1 on EVs reduced Tex^term cell infiltration and BATF expression. These findings elucidate an EV-mediated immune evasion axis and reveal actionable targets to overcome immunotherapy resistance.