DECODING THE TUMOR-IMMUNE DIALOGUE: A SINGLE-CELL TRANSCRIPTOMIC MAP OF IMMUNE ESCAPE MECHANISMS IN TRIPLE-NEGATIVE BREAST CANCER

Abstract

Background: Triple-negative breast cancer (TNBC) represents the most aggressive and therapeutically challenging subtype of breast carcinoma, characterized by immune evasion and rapid progression. While immunotherapy has shown promise, resistance remains a critical barrier. This study pioneers the use of single-cell RNA sequencing (scRNA-seq) to construct an atlas of immune-tumor interactions in TNBC, revealing exclusive escape signatures.

Methods: Fresh tumor specimens from 10 treatment-naïve TNBC patients underwent scRNA-seq using the 10x Genomics Chromium platform. We identified and clustered 94,327 individual cells, including tumor, T, B, NK, dendritic, and myeloid populations. Ligand-receptor pair analysis, pathway enrichment, and pseudotime modeling were performed to trace the trajectory of immune suppression.

Results: We identified a rare subset of tumor-infiltrating regulatory dendritic cells (tDCregs) expressing IDO1, PD-L1, and TNFRSF14, which directly inhibited cytotoxic T-cell function. Tumor cells co-expressed MUC1, CEACAM1, and LGALS9, forming an immune checkpoint triad that suppressed T-cell receptor signaling. Notably, a stem-like CD8+ T-cell cluster (CXCL13+PD-1+TCF1+) exhibited a quiescent phenotype enriched in non-responders to checkpoint blockade therapy. Our findings define a spatial and functional immune escape module unique to TNBC.

Conclusion: This is the first study to chart the immune landscape of TNBC at single-cell resolution, unveiling novel immunosuppressive cell subsets and checkpoint axes. Our data provide a blueprint for next-generation immunotherapeutic targets and predictive biomarkers. The integration of spatial transcriptomics is underway to validate these findings and drive personalized immunotherapy for TNBC.