Progenitor-exhausted T cell as prognostic indicator in esophageal squamous cell carcinoma: illuminating their key contribution to tumor immunity

Background Despite notable advances with immune checkpoint inhibitors (ICIs) in esophageal squamous cell carcinoma (ESCC), their clinical efficacy remains limited, largely due to CD8⁺T cell exhaustion. Among these, progenitor exhausted T cells (T pex ) represent a key subset with stem cell–like features that sustain durable anti-tumor immunity. Methods We applied multi-color immunohistochemistry (mIHC) to determine the spatial distribution and clinical significance of T pex cells within the tumor microenvironment (TME) of ESCC. Publicly available single-cell RNA sequencing (scRNA-seq) datasets were further analyzed to characterize T pex cell phenotypes, differentiation trajectories, and intercellular communication networks. Results T pex cells constituted a distinct subset of infiltrating CD8⁺T cells and represented a transitional stage of the exhaustion continuum. A higher degree of T pex infiltration was significantly associated with improved overall survival in ESCC patients. Moreover, scRNA-seq data from patients treated with PD-1 blockade revealed that responders harbored markedly enriched T pex populations compared with non-responders. Conclusion Our findings identify T pex cells as a critical prognostic and immunologically active CD8⁺T cell subset in ESCC. Their abundance and functional engagement are closely associated with favorable clinical outcomes and response to PD-1 blockade. Furthermore, their stem cell-like properties may be pivotal in shaping durable anti-tumor immunity and could provide novel therapeutic targets to enhance the efficacy of PD-1-based immunotherapy.