Lactate-Driven Histone Lactylation Weakens B Cell Immunity in Tertiary Lymphoid Structures

The function of tertiary lymphoid structures (TLS), which are important locations in the tumour microenvironment that promote anti-tumor humoral immunity, is frequently depleted in advanced tumours, and the underlying mechanisms are yet unknown. Through histone lactylation, the tumour metabolite lactate modifies the epigenetic status of B cells in TLS, thereby compromising their immunological activity. We used single-cell RNA sequencing, chromatin accessibility studies, and microscopic dissection of mature TLS from clinical non-small cell lung cancer tissues and animal tumour models. Lactate concentrations within TLS were determined using targeted quantitative metabolomics, and the genome-wide H3K18 lactylation signature in B cells was mapped using CUT&Tag technology. The functional impact of histone lactylation on B cell antibody generation and anti-tumor efficacy was assessed utilising adoptive transfer procedures, B cell receptor lineage tracing, and immunofluorescence in a mouse model with B cell-specific deletion of lactate dehydrogenase A. High lactate concentrations in the tumour microenvironment cause TLS-B cells to abnormally concentrate H3K18 lactylation in immunoglobulin class switch recombination sites and promoters of genes linked to somatic hypermutation. IgG2b/c class switching and affinity maturation are prevented by this epigenetic remodelling, which directly reduces the production of activation-induced cytidine deaminase and essential transcription factors. According to functional studies, mature germinal center responses in TLS can be restored by suppressing lactylation reading proteins or preventing lactate metabolism in B cells. This greatly improves antibody-dependent tumour killing and reverses resistance to immune checkpoint blockade therapy. The “lactate-histone lactylation” axis is identified in this study as a novel metabolic checkpoint for B cell immunity within TLS. This discovery reveals a pathogenic pathway by which the immunosuppressive microenvironment takes control of humoral immunity at the epigenetic level and offers specific targets for the development of combination immunotherapies aimed at restoring TLS functionality.