B cell–reactive neoantigens boost antitumor immunity

B cell involvement in neoantigen-driven antitumor immunity remains largely unexplored because of challenges in predicting B cell responses. Here, we developed a method to identify B cell epitopes by characterizing?>437,000 peptides tested for IgG binding and?>370 million B cell receptor (BCR) clones. Our single-cell BCR sequencing of pre– and post–severe acute respiratory syndrome coronavirus 2 vaccination validates the performance of this method. Mouse vaccination experiments demonstrate that B cell neoepitopes enhance immune responses, driving BCR expansion and tumor regression. Genomic analysis of?>8000 The Cancer Genome Atlas (TCGA) samples reveals an inverse correlation between predicted B cell reactivity and mutation allele frequencies, indicating B cell–mediated neoantigen elimination. Applying our multiomics model to checkpoint blockade responses in 2074 patients highlights the clinical relevance of B cell neoepitope prediction. A meta-analysis of 11 personalized vaccine trials involving 1739 neoantigens suggests that incorporating B cell neoepitopes may improve vaccination efficacy. These results underscore the significance of B cell–reactive neoantigens in antitumor immunity.