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

Area of Science:

• Cancer biology
• Metabolic reprogramming
• Epigenetics

Background:

• Cancer-associated fibroblasts (CAFs) are key drivers of tumor malignancy.
• Current therapies targeting CAF signaling molecules are often ineffective due to CAF heterogeneity.
• Metabolic reprogramming of CAFs presents a promising therapeutic avenue for colorectal cancer (CRC).

Purpose of the Study:

• To investigate the metabolic reprogramming of CAFs in CRC.
• To elucidate the role of histone lactylation in CAF-driven CRC progression.
• To explore therapeutic strategies targeting CAF lactylation in CRC.

Main Methods:

• Metabolomic and single-cell RNA-sequencing analyses were performed.
• Fibroblast-specific conditional Ldha knockout mouse models were utilized.
• Histone lactylation levels and downstream signaling pathways were investigated.

Main Results:

• CAFs exhibit increased glycolysis, intracellular lactate, and histone lactylation compared to normal fibroblasts.
• Elevated histone 3 lysine 18 lactylation (H3K18la) in CAFs promotes myofibroblastic transition, collagen deposition, and tumor growth.
• CAF histone lactylation limits CD8+ T cell infiltration and exacerbates T cell exhaustion.
• The RhoA/ROCK1/MLC2/MRTF-A pathway and ECM remodeling are crucial for CAF-driven tumor promotion.
• Cancer cell-derived TGF-β accelerates CAF metabolic reprogramming and histone lactylation.
• The clinical drug Stiripentol enhances immunotherapy efficacy in CRC models.

Conclusions:

• Elevated lactate in CAFs reprograms the epigenetic landscape, promoting CRC progression and immunosuppression.
• Targeting CAF histone lactylation is a potential therapeutic strategy for CRC.
• Understanding CAF metabolic reprogramming is critical for developing effective CRC treatments.