Regulatory B cells and <i>SIVA1-LAG3</i> immune suppression predict poor prognosis in prostate cancer

Prostate cancer (PCa) is among the most prevalent malignancies affecting men globally. The immunosuppressive characteristics of the tumor microenvironment significantly hinder the effectiveness of immunotherapeutic strategies. B cells have a dual role in immune responses, with regulatory B cells (Bregs) promoting immune tolerance through the secretion of immunosuppressive cytokines, facilitating tumor immune evasion. However, the specific role of Bregs in prostate cancer remains inadequately understood. In this study, we systematically identified Breg subpopulations in prostate cancer using single-cell RNA sequencing (scRNA-seq), multi-omics analysis, and machine learning techniques, while also investigating their association with clinical prognosis. Our analysis revealed that increased infiltration of Bregs is strongly correlated with shorter biochemical recurrence-free survival (BCRFS). Additionally, higher expression levels of SIVA1 apoptosis-inducing factor (SIVA1) were positively associated with the immune checkpoint lymphocyte-activation gene 3 (LAG3). Utilizing Breg-related prognostic genes (BRPGs), we developed a novel model for predicting BCRFS, which we validated across multiple independent cohorts. Further immunohistochemical analysis confirmed the positive correlation between elevated SIVA1 expression and poor prognosis, as well as its association with LAG3. Collectively, these findings provide new insights into the immune microenvironment of prostate cancer and suggest that Breg-related characteristics and the SIVA1-LAG3 relationship in tumor cells may represent promising therapeutic targets for future research.