Tissue-resident memory B cells augment local anti-cancer immunity via IgA

Tissue-resident memory B cells (B _RM ) provide powerful localized protection against microbial infection in barrier tissues. It is unknown if analogous B _RM populations survey solid tumors and contribute to anti-cancer immunity. We profiled B cells from patients with colorectal cancer and cutaneous basal cell carcinoma and identified a CD69 ⁺ memory B cell population consistent with a tissue-resident phenotype. Integrative analysis of transcriptomic datasets identified an optimized signature enriched across cancer types. Tumor infiltrating B _RM -like cells preferentially exhibited autoreactivity and their signature correlated with patient outcomes and response to immunotherapy. Skin and lung targeted vaccination established localized B _RM that provided IgA dependent organ specific protection upon tumor challenge in murine models. These findings establish B _RM as an active component of anti-cancer immunity via preferential reactivity to tumor associated self-antigens.