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Despite the presence of B cells in CRC infiltrate, their clinical significance is poorly understood. In this study, we observed an enrichment of double-negative (DN) B cells, a subset lacking surface IgD and CD27, in CRC biopsies. Typically underrepresented in physiological conditions, DN B cells expand in certain chronic infections, autoimmune diseases, and cancers. Within this subpopulation, low CD21 expression\u2014a phenotypic hallmark of exhaustion\u2014was observed. Consistently, DN B cells displayed low metabolic activity. Accordingly, total B cells infiltrating CRC tissues showed a diminished capacity to differentiate into antibody-secreting cells (ASCs) upon stimulation. In the murine setting, CRC organoids decreased the frequency of ASCs in co-cultured B cells and induced metabolic dysfunction, marked by altered glucose and fatty acid uptake and dysregulated expression of key metabolic proteins. Moreover, B cells displayed reduced glycolysis and mitochondrial respiration, despite increased mitochondrial dependence. This study provides evidence for DN B cell accumulation within CRC infiltrate and metabolic reprogramming of B cells, suggesting that targeting B cell metabolism may represent a promising strategy to potentiate anti-tumor immune responses.<\/jats:p>","DOI":"10.1038\/s41598-026-41446-x","type":"journal-article","created":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T04:07:48Z","timestamp":1772251668000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Immunophenotypic skewing of B cells toward IgD\u207bCD27\u207bIgG\u207a subtype and metabolic attenuation in colorectal cancer"],"prefix":"10.1038","volume":"16","author":[{"given":"Eleonora","family":"Martinis","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Tonon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viviana","family":"Valeri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Colamatteo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina","family":"Ricci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caterina","family":"Trevisan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleonora","family":"Capezzali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Pivetta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serena","family":"Battista","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Mozzon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Uzzau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Matarese","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Cossarizza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Frossi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Pucillo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,28]]},"reference":[{"key":"41446_CR1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers16081530","volume":"16","author":"G Roshandel","year":"2024","unstructured":"Roshandel, G., Ghasemi-Kebria, F. & Malekzadeh, R. 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