Background Occult breast cancer (OBC) presents with axillary lymph node (ALN) metastases without detectable primary tumor (PT) yet exhibits paradoxically favorable prognosis compared to non-occult breast cancer (non-OBC). We aimed to elucidate mechanisms underlying PT clearance by integrating multi-omics approaches to characterize the unique immune landscape. Methods Survival outcomes were validated using the Surveillance, Epidemiology, and End Results (SEER) database (n=12,162) with propensity score matching (PSM). Molecular features were characterized via quantitative proteomics, while immune landscapes were assessed using bulk transcriptomics. Single-cell RNA sequencing (scRNA-seq) and CellChat analysis dissected cellular heterogeneity and intercellular communication within tumor microenvironment. Results Survival analysis confirmed OBC patients have survival comparable to T1N+M0 but significantly better than T2–3N+M0 breast cancer (BC) patients. Proteomic profiling identified B cell-related pathway upregulation in OBC lymph nodes (LN). Transcriptomics revealed enriched B cell infiltration in T1 tumors correlating with improved survival. scRNA-seq further demonstrated that B cells in T1 tumors act as central hubs in intercellular communication. These cells orchestrate a robust anti-tumor response via multi-faceted secretory signals (e.g., tumor necrosis factor, TNF; B-cell activating factor, BAFF) and contact-dependent interactions (e.g., CD40; major histocompatibility complex, MHC), effectively recruiting and activating immune effectors. Conclusion Our findings suggest that B cell-mediated immune surveillance may be a key mechanism contributing to the clearance of PT in OBC. These exploratory results underscore the potential of B cells as prognostic biomarkers and therapeutic targets in BC, pending functional validation in larger cohorts.
Liu et al. (2026) studied this question.