Tumor-infiltrating lymphocytes display prognostic signatures associated with chemotherapy response in TNBC patients

Triple-negative breast cancer (TNBC) is an aggressive subtype often resistant to neoadjuvant chemotherapy (NAC), and tumor-infiltrating lymphocytes (TILs) are important predictors of response. Using single-cell RNA sequencing datasets of pre-treated TNBC tumors, we identified an 80-gene TIL-specific signature that captures immune activation and stratifies tumors by TIL abundance. Pathway analysis showed enrichment of immune-regulatory programs, including allograft rejection, consistent with adaptive immune activity. Validation across single-cell and bulk datasets linked the signature to favorable response and relapse-free survival. A multi-stage feature selection pipeline refined the panel to 30 genes, achieving strong prediction of pathological complete response versus residual disease across eleven independent TNBC cohorts (n = 680; mean area under the ROC curve [AUROC] = 0.77). Network analysis identified consensus hub genes, including CD8A, LCK, and CTLA4, central to T cell signaling. Regulatory analysis revealed a conserved set of TIL-associated transcription factors, supporting an immune program with clinical utility in TNBC stratification and therapeutic targeting strategies.