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Tumor-intrinsic PHGDH inhibition rewires macrophage epigenetic programs to sensitize colorectal cancer to PD-1 blockade

ABSTRACT: Metabolic reprogramming in tumor cells profoundly shapes the tumor microenvironment (TME) and limits the efficacy of immunotherapy in colorectal cancer (CRC). However, how tumor-intrinsic metabolic alterations orchestrate immune remodeling remains poorly understood. Here, we identify phosphoglycerate dehydrogenase (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 α-ketoglutarate (α-KG) levels in the TME and subsequent epigenetic remodeling of tumor-associated macrophages. Mechanistically, α-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.

ORGANISM(S): Mus musculus

PROVIDER: GSE325746 | GEO | 2026/03/31

REPOSITORIES: GEO

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