INTRODUCTION Tumor-derived lactic acid (LA) plays a dual role in shaping the immunosuppressive tumor microenvironment by directly modulating immune cell function. OBJECTIVES Tumor-infiltrating B cells enhance antitumor immunity by promoting T-cell proliferation, whereas immunosuppressive subsets such as regulatory B cells (Bregs) counteract these effects via IL-10 sretion. However, the metabolic impact of lactate on B-cell functionality remains unclear. METHODS Using flow cytometry, we analyzed LA-induced phenotypic alterations in B cells and assessed Breg immunosuppressive activity via suppression assays. The tumor-inhibitory effects of blocking lactate receptor signaling were examined in animal models. RESULTS Here, we reveal a previously unrecognized immunosuppressive mechanism mediated by CD25+CD81+ B cells (Bregs) in lung cancer. In murine models, LA induced ROS production in splenic and intratumoral Bregs through G protein-coupled receptor 81 (GPR81) signaling, thereby suppressing T-cell responses. Mechanistically, LA binding to GPR81 activates the cAMP/TAZ/PPARα axis, which orchestrates ROS generation in Bregs. Genetic ablation of lactate dehydrogenase A (LDHA) in tumor cells disrupted this signaling cascade in vivo, resulting in reduced ROS levels and restored T-cell activity. Pharmacological inhibition of GPR81 or PPARα similarly attenuated Breg-mediated immunosuppression and delayed tumor progression. Clinically, we identified ROS+ Breg populations in lung cancer patients, and elevated tumor LDHA expression correlated with poor prognosis. CONCLUSION Our findings establish the LA-GPR81/TAZ/PPARα/ROS axis in Bregs as a redox-dependent checkpoint for tumor immune evasion, and highlighting novel therapeutic targets for lung cancer immunotherapy.
