Single-cell RNA sequencing reveals immune microenvironment heterogeneity in BRCA1-mutated and sporadic triple-negative breast cancer.

Immune checkpoint blockade has shown benefit in some Triple-negative breast cancer (TNBC) patients, but responses are variable. BRCA1-mutated TNBC represents a biologically distinct subgroup, potentially differing in immunogenicity and immunotherapy responsiveness. However, immune microenvironment differences between BRCA1-mutated and sporadic TNBC remain incompletely understood. By performing single-cell RNA sequencing analysis on sporadic TNBC and BRCA1 mutant TNBC, we assessed immune cell composition, transcriptional program, pathways, stemness, differentiation, and transcription factor regulatory networks. B cell and plasma cell subtypes were further explored using AUCell, CytoTRACE, Monocle2, and Slingshot. Compared to sporadic TNBC, BRCA1-mutated TNBC exhibited a distinct immune landscape with enriched naïve and memory B cells, while sporadic TNBC was dominated by terminally differentiated plasma cells, including IgA plasma cells. Functional enrichment analyses showed enhanced adaptive immune signaling, antigen presentation, and B cell receptor pathways in BRCA1-mutated TNBC, while sporadic TNBC had humoral effector and immunoregulatory programs. Trajectory and stemness analyses indicated enhanced cellular plasticity and decreased differentiation in B cells derived from BRCA1-mutated triple-negative breast cancer. Analysis of transcription factors revealed JUND and ETV1 in BRCA1-mutated TNBC, and MEIS1 and CEBPB in sporadic TNBC. Our findings underscore disparities in the immune ecosystem between BRCA1-mutated and spontaneous TNBC, indicating that the B cell-centric immunological milieu in BRCA1-mutated TNBC may offer a more advantageous setting for immunotherapy. Sporadic TNBC, by contrast, exhibits an immunological state characterized by plasma cells, which may restrict immune reactivation. These data indicate that B cell-based immunological stratification may guide precision immunotherapy approaches.