Regulatory B cells: changing the landscape of immunoregulation and immunotherapy

Recent advances in understanding regulatory B cells (Bregs) as critical modulators of immune homeostasis have opened new avenues for therapeutic intervention across a broad spectrum of immune-mediated diseases. Despite compelling preclinical evidence, Breg-targeted therapies have not yet entered clinical practice. Distinct Breg subpopulations employ diverse mechanisms of immunosuppression, and this heterogeneity allows for more precise selection of proper Breg subsets for therapeutic use in specific pathological contexts. This article provides a comprehensive overview of the current state of Breg field, highlighting their cytokine- and checkpoint-mediated suppressive mechanisms, as well as emerging insights into the role of metabolism in shaping Breg differentiation and function. Strategies for in vivo Breg induction are outlined along with cutting-edge techniques for generating and expanding Bregs ex vivo. Furthermore, we explore how current immunotherapies, such as therapeutic antibodies targeting Breg-associated markers and effector molecules, affect their heterogeneity and functionality, highlighting the potential synergies and antagonisms between these therapies and Breg-mediated immunoregulation. Finally, we discuss current limitations in the field that lie ahead in translating these strategies into clinical reality and highlight future directions for advancing Breg-based immunotherapies.