Lactate Blocks Tertiary Lymphoid Structure Formation by Inhibiting B Cell Chemotaxis

Abstract Tertiary lymphoid structures (TLS) and B cell infiltration are strong predictors of immunotherapy success across cancers, including triple-negative breast cancer (TNBC). However, immune-cold TNBCs often lack both features. Here, we identify a tumor-intrinsic mechanism that actively suppresses B cell recruitment. Despite evidence of B cell responses in cancer-associated lymph nodes (cLNs), B cells fail to infiltrate TNBC tumors or form TLS. This exclusion is not simply due to chemokine deficiency as exogenous chemokine addition fails to restore B cell migration. Using fractionation and metabolic profiling, we identify lactate as a dominant tumor-secreted metabolite that directly impairs B cell chemotaxis by disrupting mitochondrial metabolism. In vivo, combining lactate inhibition with engineered chemokine secretion promotes cLN-derived B cell infiltration and enables TLS formation, particularly when coupled with CD40 stimulation. Transcriptomics analyses across several human cancer datasets strengthen the association between high glycolytic activity with poor B-cell infiltration in chemokine-rich tumors. Together, our findings reveal lactate as a key metabolic barrier to B cell trafficking and TLS induction, suggesting that metabolic reprogramming may provide an avenue to convert “immune-cold” tumors into TLS-rich, immunologically responsive microenvironments. Competing Interest Statement A.G. CEO Pharos AI; D.P.C. is named inventor on a patent relating to synthetic lethality of NMT inhibitors in high-MYC cancers (WO2020128475); D.P.C. and M.S.H. are named inventors on a patent relating to Follicular Lymphoma biomarker signature (GB2509744.5). D.P.C. research funding from AstraZeneca. These competing interests are unrelated to this work. A.G. and D.P.C. Research funding - Boehringer Ingelheim. This competing interest is related to this work. All other authors declare no competing interests.