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Tumor-draining lymph nodes (TDLNs) are key immunological sites where anti-tumor responses are orchestrated, yet the prognostic relevance of B cell phenotypes in TDLNs remains underexplored. TDLNs from 49 OSCC patients treated at Karolinska University Hospital were prospectively analyzed. Single-cell suspensions were examined using multicolor flow cytometry to characterize B cell subsets (na\u00efve, memory, plasma cells) and expression of immunoregulatory markers (CD11c, CD24, CXCR5, CD73, HLA-DR, PD-L1). B cell profiles were correlated with clinical outcomes, including disease-free survival (DFS) and overall survival (OS). Disease-free patients exhibited a distinct B cell profile marked by a higher proportion of na\u00efve B cells, strong CXCR5 and CD11c expression, and increased plasma cell differentiation. Recurrence was associated with elevated CD24, CD73, and HLA-DR expression, markers linked to immunoregulatory or dysfunctional B cell states. Interestingly, high PD-L1 expression on memory B cells correlated with improved prognosis, suggesting a context-dependent immune function. In line with these observations, multivariate analysis confirmed HLA-DR expression, together with nodal status, as independent prognostic factors for survival in OSCC. B cell phenotypes in OSCC TDLNs are strongly associated with patient outcomes. A microenvironment enriched in na\u00efve and functionally active B cells supports durable tumor control, whereas regulatory\/exhausted phenotypes are linked to recurrence. These findings position B cell markers as promising prognostic indicators and therapeutic targets in OSCC, warranting validation in larger cohorts and functional studies.<\/jats:p>","DOI":"10.1007\/s00262-025-04231-9","type":"journal-article","created":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T13:16:16Z","timestamp":1762953376000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["B Cell dysfunction in tumor-draining lymph nodes predicts relapse in oral squamous cell carcinoma"],"prefix":"10.1007","volume":"74","author":[{"given":"Vilma","family":"Liljestr\u00f6m","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pedro","family":"Farrajota Neves da Silva","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rusana","family":"Bark","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexandra","family":"Elliot","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linda","family":"Marklund","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gregori","family":"Margolin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susanna","family":"Kumlien Geor\u00e9n","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lars-Olaf","family":"Cardell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Krzysztof","family":"Piersiala","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,11,12]]},"reference":[{"issue":"1","key":"4231_CR1","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1038\/s41572-020-00224-3","volume":"6","author":"DE Johnson","year":"2020","unstructured":"Johnson DE, Burtness B, Leemans CR, Lui VWY, Bauman JE, Grandis JR (2020) Head and neck squamous cell carcinoma. 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