Tumor-intrinsic PHGDH inhibition sensitizes colorectal cancer to PD-1 blockade via α-ketoglutarate-mediated macrophage reprogramming.

Abstract

Metabolic reprogramming of tumor cells profoundly shapes the tumor microenvironment and contributes to immunotherapy resistance in colorectal cancer (CRC). Here, we identify phosphoglycerate dehydrogenase (PHGDH), a rate-limiting enzyme in de novo serine biosynthesis, as a metabolic regulator of antitumor immunity. In syngeneic CRC models, pharmacological PHGDH inhibition enhanced the efficacy of PD-1 blockade, while genetic PHGDH silencing recapitulated the major immunometabolic effects of WQ-2101. Single-cell transcriptomic and functional analyses showed that tumor-cell PHGDH inhibition suppressed serine metabolism and reduced tumor-derived α-ketoglutarate availability, thereby reprogramming tumor-associated macrophages toward an inflammatory, antigen-presenting phenotype. Mechanistically, reduced α-ketoglutarate attenuated KDM5B-mediated H3K4 demethylation, preserving H3K4me3 enrichment at STAT1 target promoters, including Nos2 and Cxcl9, and activating JAK-STAT1 signaling. These reprogrammed macrophages enhanced CD8⁺ T-cell infiltration and cytotoxicity, thereby augmenting antitumor immunity and sensitizing tumors to PD-1 blockade. In a retrospective cohort of 51 patients with CRC receiving immune checkpoint inhibitor (ICI)-based therapy, lower tumor PHGDH expression was associated with a higher response rate, longer progression-free survival, increased CD8⁺ lymphocyte density, and a higher proportion of CD68⁺iNOS⁺ macrophages. Collectively, these findings define a tumor-macrophage metabolic-epigenetic circuit through which PHGDH-dependent metabolic cues regulate macrophage state and antitumor immunity, supporting PHGDH as a potential therapeutic target and a candidate outcome-associated biomarker in patients with CRC receiving ICI-based therapy.