Breast cancer is a leading cause of cancer-related mortality, with tumor heterogeneity and drug resistance posing significant challenges to treatment. We integrated single-cell RNA sequencing, spatial transcriptomics, and bulk RNA-seq deconvolution to analyze BRCA samples. Our analysis identified 15 major cell clusters, including neoplastic epithelial, immune, stromal, and endothelial populations. Notably, low-grade tumors showed enriched subtypes, such as CXCR4+ fibroblasts, IGKC+ myeloid cells, and CLU+ endothelial cells, with distinct spatial localization and immune-modulatory functions. These subtypes were paradoxically linked to reduced immunotherapy responsiveness, despite their association with favorable clinical features. High-grade tumors exhibited reprogrammed intercellular communication, with expanded MDK and Galectin signaling. Bulk RNA-seq deconvolution further supported the prognostic significance of low-grade-enriched subtypes. Our findings highlight the heterogeneity of the tumor microenvironment and provide new insights into immune evasion and therapeutic resistance in breast cancer.
Kuang et al. (Tue,) studied this question.