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

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.