Tumor-intrinsic PHGDH inhibition rewires macrophage epigenetic programs to sensitize colorectal cancer to PD-1 blockade
Metabolic reprogramming in tumor cells profoundly shapes the tumor microenvironment and limits the efficacy of immunotherapy in CRC. However, how tumor-intrinsic metabolic alterations orchestrate immune remodeling remains poorly understood. Here, we identify PHGDH, a key enzyme in the serine biosynthesis pathway, as a critical metabolic regulator of antitumor immunity. Pharmacological inhibition and genetic suppression of PHGDH significantly enhanced the therapeutic response to PD-1 blockade in CRC models. Integrated single-cell transcriptomic analyses revealed that PHGDH inhibition reprograms tumor metabolism, leading to reduced alpha-KG levels in the TME and subsequent epigenetic remodeling of tumor-associated macrophages. Mechanistically, alpha-KG depletion suppresses KDM5B activity, maintains H3K4me3 enrichment at STAT1 target promoters, and activates JAK-STAT1 signaling, thereby promoting macrophage inflammatory polarization with augmented antigen-presenting capacity. These reprogrammed macrophages promote CD8+ T cell infiltration and cytotoxic function, ultimately amplifying antitumor immunity and sensitizing tumors to ICB. Consistently, clinical analyses demonstrate that low PHGDH expression correlates with an immune-active phenotype and improved immunotherapy outcomes. Collectively, our findings uncover a tumor-macrophage metabolic-epigenetic crosstalk that governs immune responsiveness and highlight PHGDH as a promising therapeutic target and candidate biomarker for immunotherapy in CRC.