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

Authors

Chaofan Peng, Tuo Wang, Zhihao Chen, Sheng Yang, Chi Jin, Ye Wang, Dingnan Meng, Wen Peng, Yifei Feng, Peng Yang, Yueming Sun

Published in

Cancer research. Aug 05, 2026. Epub Aug 05, 2026.

Abstract

Cancer-associated fibroblasts (CAFs) 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 (CRC). Here, we conducted metabolomic and single-cell RNA-sequencing analyses that uncovered increased glycolysis, intracellular lactate, and histone lactylation in CAFs compared to normal fibroblasts (NFs). Elevated histone 3 lysine 18 lactylation (H3K18la) in CAFs promoted the transition of CAFs to myofibroblastic CAFs (myCAFs), increased collagen deposition, and enhanced organoid growth. Furthermore, fibroblast-specific conditional lactic dehydrogenase A (Ldha) knockout in a mouse model mitigated CRC tumorigenesis and progression in vivo. Cancer cell-derived TGF-β accelerated metabolic reprogramming and histone lactylation in CAFs. NPM1, a histone chaperone functioning as a cofactor of P300, enhanced the H3K18la level of the ROCK1 promoter and activated ROCK1 transcription. The RhoA/ROCK1/MLC2/MRTF-A pathway and extracellular matrix (ECM) remodeling were indispensable for the tumor-promoting effect of CAF histone lactylation in CRC. Furthermore, 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 CRC 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 CRC.

PMID:
42554434
Bibliographic data and abstract were imported from PubMed on 05 Aug 2026.

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