Sodium butyrate inhibits colorectal cancer development by reducing M2 macrophage polarization and PD-L1 expression

Abstract

CRC remains a leading cause of cancer death worldwide, and new therapeutic approaches are urgently needed. Our study reveals that NaB, a natural gut‐derived metabolite, can reshape the tumor immune environment by limiting pro‐tumor M2 macrophages and reducing PD-L1 + macrophage infiltration. By combining single‐cell transcriptomics with mouse models, we pinpoint how butyrate acts through the HDAC/TLR4/MyD88 pathway and demonstrate its synergy with PD-L1 blockade. These findings highlight butyrate’s potential as an accessible, low-toxicity agent to boost existing immunotherapies and offer a clear rationale for clinical trials exploring butyrate–immune checkpoint inhibitor combinations in CRC.