SMARCA5 links histone lactylation to metabolic reprogramming and immune evasion [CUT&Tag]

Lysine lactylation is a lactate-induced post-translational modification that links cellular metabolism to biological processes. However, the functional role of this histone mark in cancers remains largely unexplored, partly due to a lack of knowledge about its reader proteins. Here, we identify SMARCA5 as a bona fide effector of H3K18la. Transcriptomics, metabolomics and epigenetics analyses reveal numerous SMARCA5 target genes, enriched for metabolic regulators including HK2, PFKM, and LDHA. We further demonstrate that SMARCA5 facilitates glycolytic activity by recruiting MYC to the promoters of glycolytic genes. Elevated lactate derived from tumor glycolysis similarly increases H3K18la levels in CD8+ T cells and induces inhibitory receptor expression. Consequently, the glycolysis/H3K18la/SMARCA5/MYC positive feedback loop exacerbates tumor metabolism and promotes immune evasion. Pharmacologic inhibitor of LDHA that interrupts this loop attenuates immune evasion and sensitizes cancer cells to immunotherapy. Collectively, we propose SMARCA5 as a bona fide H3K18la reader that promotes tumor progression and immune escape by coupling cellular metabolism to epigenetic regulation.