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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.<\/jats:p>","DOI":"10.1038\/s41392-026-02902-2","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T00:01:37Z","timestamp":1787097697000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Humoral immunity in cancer"],"prefix":"10.1038","volume":"11","author":[{"given":"Jeanne","family":"Leonard","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4006-5605","authenticated-orcid":false,"given":"Marie","family":"Duhamel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4318-0817","authenticated-orcid":false,"given":"Michel","family":"Salzet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,19]]},"reference":[{"key":"2902_CR1","first-page":"357","volume":"74","author":"H Bence Jones","year":"1850","unstructured":"Bence Jones, H. 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