Immunophenotypic skewing of B cells toward IgD⁻CD27⁻IgG⁺ subtype and metabolic attenuation in colorectal cancer

Colorectal cancer (CRC) is the third most prevalent cancer and understanding its tumor microenvironment (TME) is crucial for the development of innovative therapies. 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-a phenotypic hallmark of exhaustion-was 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.