B cell immunity and therapeutic opportunities in brain metastases

Arising from extracranial cancers, brain metastases (BrM) are the most prevalent brain malignancy in adults. Even though there are recent advances in systemic cancer therapies and immunotherapies, the prognosis for BrM remains poor, with median survival rather dismal. The central nervous system (CNS) presents a distinct immunological and structural landscape that restricts immune surveillance and effective therapeutic delivery. This immune privilege is enforced by the blood brain barrier (BBB), specialized myeloid populations, in conjunction with reduced lymphatic drainage, which collectively constrains the effector immune cell trafficking and antigen presentation. Thus, immunotherapeutic strategies that have revolutionized systemic oncology, such as immune checkpoint inhibitors (ICIs) and chimeric antigen receptor (CAR)-T cell therapies, have presented only rather modest benefit in BrM. While immunotherapy-focused research has largely focused on T-cell-mediated mechanisms, an accumulation of recent findings suggest that B cells play multifaceted and underexplored roles within the unique CNS tumor microenvironment (TME). Aside from antibody production, B cells contribute to antigen presentation, cytokine secretion, and the formation of tertiary lymphoid structures which are functions that can either promote or suppress antitumor immunity depending on their differentiation state and local cues. In primary brain tumors, like glioblastoma (GBM), B cell infiltration has been linked to both enhance immune activation and immune regulation, yet their significance in BrM remains comparatively undefined. Understanding how B cells adapt and function within the niche constraints of the CNS, such as how they influence immune suppression, antigen presentation, and TME remodeling, may reveal new therapeutic vulnerabilities and allow for harnessing complementary B cell-based immunotherapies instead of T cell-focused approaches. This review synthesizes current knowledge on the structural and immunological features that differentiate BrM from primary brain tumors and extracranial metastases. We highlight the emerging evidence on B cell biology in the CNS, and discuss their immunostimulatory and immunoregulatory capacities, while exploring ongoing efforts to leverage B cell-based immunotherapies in brain malignancies, specifically proposed BrM. By defining the immunological landscape of BrM and the therapeutic promise of B cells, this work suggests a new possibility in CNS oncology, where humoral immunity may be harnessed to target brain metastatic malignancies.