A clinically relevant pan-cancer prognostic signature derived from T-cell activation immune genes: Experimental validation across malignancies with emphasis on breast cancer.

T-cell activation is widely recognized as a pivotal anti-tumor mechanism, yet emerging evidence reveals functional heterogeneity among T-cell subtypes within the tumor microenvironment (TME). To address this complexity, we developed a pan-cancer prognostic model to systematically evaluate the roles of T-cell activation-related immune response genes (TCR-IRGs) across malignancies. Pan-cancer transcriptomic data from UCSC Xena were analyzed. Through LASSO Cox regression, a prognostic signature comprising 23 TCR-IRGs was established.The high-risk score was significantly associated with aggressive malignant phenotypes, including enhanced epithelial mesenchymal transition and tumor proliferation. Further investigation focused on PTGER4, a gene within the signature predominantly expressed in T cells, as revealed by single-cell RNA sequencing analysis in breast tissues. Mechanistically, PTGER4 expression correlated with multiple immune checkpoints. In mouse models, PTGER4 overexpression enhanced the efficacy of PD-1 blockade by promoting CD8⁺ T cell infiltration and function, as indicated by increased levels of IFN-γ and Granzyme B. This study establishes a TME-centric prognostic framework, revealing that while the composite TCR-IRGs score generally indicates a higher risk of tumor progression, individual components like PTGER4 may paradoxically mark a T-cell state amenable to reinvigoration by immunotherapy, highlighting the context-dependent utility of immune biomarkers in oncology.