CAFs ‐mediated histone lactylation reprograms cholesterol metabolism in colorectal cancer to drive CD8 + T cell immunosuppression

Abstract The progression of colorectal cancer (CRC) is critically regulated by cancer‐associated fibroblasts (CAFs) within the tumor microenvironment (TME), yet the specific molecular mechanisms by which CAFs influence CRC remain unclear. This study reveals the mechanism by which CAFs promote CRC malignant progression and immune suppression through metabolic reprogramming. Findings indicate that lactate secreted by CAFs induces lactylation modifications of histone H3K9La and H3K18La, thereby upregulating the expression of key cholesterol synthesis enzymes DHCR7 and CYP51A1, which in turn enhances the malignant properties of CRC cells. In vivo and in vitro experiments confirm that inhibiting DHCR7 significantly reverses CAF‐mediated tumor promotion. More importantly, this study revealed that CAF‐induced CRC cells with elevated cholesterol metabolism deliver DHCR7 to CD8 + T cells via exosomes, thereby triggering mitochondrial dysfunction and driving the cellular senescence process. This senescence manifests as reduced IFN‐γ secretion capacity and enhanced senescence‐associated secretory phenotype (SASP). In summary, this study systematically elucidates the central role of the CAF–CRC cell–CD8 + T cell regulatory axis: CAF‐derived lactate modulates cholesterol metabolism in CRC cells via histone lactylation. Subsequently, CRC cells with enhanced cholesterol metabolism deliver DHCR7 to CD8 + T cells via exosomes, inducing mitochondrial dysfunction, which in turn leads to CD8 + T‐cell senescence and immunosuppression. This provides a new theoretical foundation and therapeutic rationale for metabolic–immune combination strategies in CRC. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.