Histone Lactylation in Cancer-Associated Fibroblasts Induces Extracellular Matrix Remodeling and Immunosuppression to Promote Colorectal Cancer Progression

Abstract Cancer-associated fibroblasts (CAF) drive key aspects of tumor malignancy. However, the profound heterogeneity in cytokine secretion and cell–cell communication orchestrated by CAFs renders therapeutic strategies targeting these molecules largely ineffective against cancer. In contrast, exploring the metabolic reprogramming mechanisms of CAFs could be conducive to therapeutic intervention in colorectal cancer. In this study, we conducted metabolomic and single-cell RNA sequencing analyses that uncovered increased glycolysis, intracellular lactate, and histone lactylation in CAFs compared with normal fibroblasts. Elevated histone 3 lysine 18 lactylation (H3K18la) in CAFs promoted the transition of CAFs to myofibroblastic CAFs, increased collagen deposition, and enhanced organoid growth. Furthermore, fibroblast-specific conditional lactic dehydrogenase A knockout in a mouse model mitigated colorectal cancer tumorigenesis and progression in vivo. Cancer cell–derived TGFβ accelerated metabolic reprogramming and histone lactylation in CAFs. Nucleophosmin 1, a histone chaperone functioning as a cofactor of P300, enhanced the H3K18la level of the rho-associated, coiled-coil–containing protein kinase 1 (ROCK1) promoter and activated ROCK1 transcription. The RhoA/ROCK1/myosin light chain 2/myocardin-related transcription factor-A pathway and extracellular matrix (ECM) remodeling were indispensable for the tumor-promoting effect of CAF histone lactylation in colorectal cancer. Additionally, CAF histone lactylation limited CD8+ T-cell infiltration and aggravated CD8+ T-cell exhaustion via ECM remodeling. Stiripentol, a clinical drug that targets lactylation, potentiated the efficacy of immunotherapy in colorectal cancer models. Together, this study demonstrates that elevated lactate levels in CAFs reprogram the epigenetic landscape to promote tumor progression and immunosuppression, highlighting the potential of targeting CAF histone lactylation as a therapeutic strategy for colorectal cancer. Significance: Cancer cell-derived TGFβ activates glycolysis in cancer-associated fibroblasts to induce histone lactylation that facilitates extracellular matrix remodeling and T cell exhaustion, identifying a metabolic-epigenetic-tumor microenvironment axis as a target to overcome immunosuppression.