Progenitor-Exhausted T Cell as Prognostic Indicator in Esophageal Squamous Cell Carcinoma: Illuminating Their Key Contribution to Tumor Immunity

Yi LiuHongwei JiangFang ZhangBin XuJunjun ChenXiao ZhengRenhao Geng^*Lujun Chen^*

• Department of Tumor Biological Treatment, First People's Hospital of Changzhou, Changzhou, China

Despite the significant progress brought by immune checkpoint inhibitors (ICIs) in treating esophageal squamous cell carcinoma (ESCC), their effectiveness remains limited due to the exhaustion of CD8⁺T cells. Within this exhausted subset, progenitor-exhausted T cells (Tpex) play a pivotal role in maintaining durable anti-tumor immunity. In this study, we employed multi-color immunohistochemistry (mIHC) to map the spatial distribution and assess the clinical relevance of tumor-infiltrating Tpex cells within the tumor microenvironment (TME) of ESCC. Additionally, leveraging publicly available single-cell RNA sequencing (scRNA-seq) datasets, we explored the functional characteristics and intercellular communication dynamics of Tpex cells in the context of ESCC. Our integrative analyses revealed that Tpex cells constituted a distinct and functionally important subset of infiltrating CD8⁺T cells, representing a key transitional stage along the T-cell differentiation trajectory. Importantly, a higher abundance of Tpex infiltration correlated significantly with improved overall survival (OS) in ESCC patients. Furthermore, analysis of scRNA-seq profiles from patients before and after PD-1 blockade therapy indicated that clinical responders exhibited a substantially enriched Tpex population. Together, these findings underscored the prognostic value of Tpex in ESCC and suggested that their stem cell-like features might be instrumental in shaping durable anti-tumor immunity.