Humoral immunity in cancer

Abstract

Abstract Humoral immunity driven by B cells, plasma cells, and antibodies has emerged as a major determinant of tumor control, immune escape, and therapeutic response. Across solid tumors, mature tertiary lymphoid structures (TLS) with high endothelial venules, follicular dendritic-cell networks, and T follicular helper cell niches support germinal-center-like reactions, B-cell receptor selection, somatic hypermutation, class-switch recombination, antigen presentation, and local humoral memory. However, B-lineage responses are not uniformly protective. Regulatory B cells, IgA- or IgG4-skewed plasma cells, inhibitory Fc-receptor signaling, chronic immune complexes, and tumor-imposed metabolic stress can suppress cytotoxic immunity and reprogram myeloid compartments. This review synthesizes the mechanisms that determine whether humoral immunity is antitumor or protumor, including TLS maturity, B-cell and plasma-cell states, antibody subclass and tissue geography, Fc glycosylation, Fc-receptor balance, complement context, immunometabolic adaptation, and spatial organization. We also discuss how single-cell, B-cell receptor repertoire, spatial transcriptomic, and spatial proteomic approaches can resolve antigen-driven B-cell selection and distinguish TLS-organized effector niches from diffuse regulatory infiltrates. Finally, we map current and emerging therapeutic strategies, from approved B-cell and antibody-directed agents in hematologic malignancies to TLS-inducing, Fc-engineering, vaccine, and isotype-modulating approaches in solid tumors, and we propose biomarker-guided guardrails for clinical translation. These guardrails are intended to preserve protective TLS-linked immunity while selectively targeting suppressive humoral programs.