B lymphocytes exhibit dual roles in tumorigenesis, acting as both allies and adversaries in the tumor microenvironment (TME). Their anti-tumor functions include recognizing tumor-associated antigens, producing antibodies, activating cytotoxic immune responses, and forming tertiary lymphoid structures (TLS) that enhance immune cell coordination. Tumor-infiltrating B cells (TIL-Bs) within TLS contribute to improved patient survival and immunotherapy responses by facilitating antibody class switching, somatic hypermutation, and cytokine secretion that recruit and activate T cells, natural killer (NK) cells, and dendritic cells (DCs). Antibodies from B cells mediate complement-dependent cytotoxicity (CDC), antibody-dependent cellular phagocytosis (ADCP), and antibody-dependent cell-mediated cytotoxicity (ADCC), directly eliminating tumor cells. Additionally, B cells present antigens to T cells and secrete cytokines like IFN-γ and CXCL13, amplifying anti-tumor immunity. However, regulatory B cells (Bregs) and other subsets suppress immune responses by secreting IL-10, TGF-β, and VEGF, promoting angiogenesis, recruiting immunosuppressive cells like myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), and expressing immune checkpoints like PD-L1. This duality underscores the complexity of targeting B cells in cancer therapy.

Clinical evidence highlights the prognostic significance of B cell infiltration. TLS-associated B cells correlate with better outcomes in melanoma, renal cell carcinoma, and hepatocellular carcinoma, while Bregs are linked to tumor progression in gastric, pancreatic, and head-and-neck cancers. Single-cell sequencing reveals heterogeneous B cell subsets, including plasma cells, follicular B cells, and cytotoxic "killer B cells," each with distinct roles. For instance, germinal center (GC) responses dominate in colorectal cancer, while extrafollicular (EF) responses prevail in liver cancer. TIL-Bs also enhance T cell infiltration and activation, particularly in immunogenic "hot" tumors. However, Bregs impair NK cell function via STING-IL-35 signaling and inhibit DC maturation, creating an immunosuppressive niche. Tumor-promoting antibodies produced by Bregs activate pro-inflammatory pathways or bind tumor surface receptors, fostering metastasis in breast and gastric cancers.

Emerging immunotherapies aim to exploit B cell functions while mitigating their pro-tumor effects. Immune checkpoint inhibitors (ICIs) like anti-PD-1/PD-L1 enhance B cell activation and TLS formation but risk autoimmune side effects. Monoclonal antibodies (mAbs) such as rituximab deplete CD20+ B cells, yet indiscriminate depletion may inadvertently enrich Bregs. Strategies to enhance B cell anti-tumor activity include CD40 agonists, TLR9 adjuvants, and vaccines targeting HER2 or NY-ESO-1. Fc domain engineering improves mAb efficacy by optimizing complement activation and Fc receptor binding. Conversely, inhibiting Bregs via BTK inhibitors or STAT3/MEK pathways shows promise in preclinical models. Challenges remain in identifying precise B cell subsets, understanding signaling networks, and balancing immune activation with tolerance.

Future directions emphasize decoding B cell heterogeneity, developing precision therapies, and overcoming tumor evasion mechanisms. Key priorities include defining molecular markers for pro- and anti-tumor subsets, elucidating regulatory pathways like PD-1/PD-L1 interactions, and engineering strategies to enhance antibody specificity against tumor-associated self-antigens. Combining B cell-targeted therapies with ICIs or adoptive T cell transfer may synergize anti-tumor responses. However, tumor-induced immune suppression, antigen loss, and chronic inflammation-driven B cell dysfunction pose hurdles. Addressing these requires integrating multi-omics data, spatial transcriptomics, and functional studies to unravel context-dependent B cell behaviors. Ultimately, harnessing B cells’ dual nature demands a nuanced approach to tip the balance toward sustained anti-tumor immunity while minimizing unintended immunosuppression.

The interplay between B cells and the TME remains a frontier in cancer immunology. While their antibody-producing and antigen-presenting capacities offer therapeutic avenues, their plasticity necessitates careful modulation. Advances in single-cell profiling, neoantigen discovery, and combinatorial therapies hold potential to unlock B cells’ full anti-tumor potential, transforming them from unpredictable players into precision tools in the fight against cancer.
DOI: 10.1007/s11684-025-1127-5