Tumor-associated macrophages (TAMs) exhibit heterogeneous properties including anti-tumorigenic and pro-tumorigenic phenotypes. The rate-limiting enzyme in de novo serine biosynthesis, 3-phosphoglycerate dehydrogenase (PHGDH), has a well-established role in cellular metabolism, yet its specific role in macrophages remains unknown.

Metabolomics assays were conducted to assess metabolite composition and dynamics in macrophages. Changes in polarization and immunosuppressive markers were validated with qRT-PCR. Bioinformatics was used to analyze immune cell subsets and associated metabolic pathways. Finally, ChIP-qPCR and co-immunoprecipitation assays were performed to elucidate the downstream regulatory mechanisms of PHGDH.

Serine metabolism was found to be downregulated in TAMs in breast cancer. Functional studies revealed that PHGDH inhibition promotes an M2-like phenotype and immunosuppressive functions in macrophages. Furthermore, PHGDH was found to undergo nuclear translocation during macrophage polarization. Mechanistically, nuclear PHGDH was found to regulate GLUD1 and GLS2 transcription via interaction with the transcription factor STAT3. Rescue experiments demonstrated that glutamine supplementation and STAT3 inhibition reversed the effects of PHGDH on macrophage function.

Our findings reveal a previously unrecognized non-canonical metabolic function of PHGDH, thus providing potential therapeutic targets in the tumor microenvironment for reversing malignant progression.