Histone H4K5 lactylation-driven feedback loop modulates glycerol-linked immunosuppressive activity of tumor-associated T regulatory cells

Abstract

Tumor metastasis is the leading cause of death for more than 90% of cancer patients, with colorectal cancer (CRC) mainly spreading to the liver. The colon and liver possess distinct nutritional microenvironments, yet how these differences shape the tumor immune landscape remains unclear. Using single-cell analysis of autologous samples from CRC patients with liver metastases, we identified a distinct CD177+GK+ regulatory T (Treg) cell subset in metastatic lesions. Spatial transcriptomics revealed that these GK+ Tregs localize at the tumor-adjacent interface and interact with immunosuppressive macrophages. Moreover, a selective clonal selection was observed in the metastatic niche, leading to the super-amplification of metastasis-associated clones of GK+ Tregs, suggesting a dominant role of these clones in metastatic immune evasion. Mechanistically, glycerol-derived lactate promotes H4K5 histone lactylation, which upregulates FOXP3 and subsequently GK expression, creating a positive feedback loop that amplifies Treg immunosuppressive activity. Blocking the glycerol metabolic pathway in Tregs combined with anti-PD-1 therapy synergistically curbs tumor progression. Pan-cancer analyses further confirm the potent suppressive activity of CD177+GK+ Tregs across multiple cancer types. Collectively, our findings highlight glycerol metabolism and histone lactylation as critical drivers of Treg-mediated immune evasion, offering new strategies to reprogram the immunosuppressive tumor microenvironment for enhanced cancer therapy.