Targeting serine-glycine-one-carbon metabolism as a vulnerability in cancers

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TL;DR

The serine-glycine-one-carbon (SGOC) metabolic pathway is frequently upregulated in cancers and supports tumor growth through nucleotide synthesis, redox balance, and epigenetic regulation. Key enzymes such as PHGDH, SHMT2, and MTHFD2 are highly expressed across multiple cancer types and are associated with poor prognosis, immune cell infiltration, and resistance to ferroptosis. Targeting SGOC metabolic enzymes with small-molecule inhibitors (e.g., NCT-503, SHIN1, pemetrexed) or dietary serine/glycine restriction represents a promising therapeutic strategy, particularly when combined with immunotherapy or ferroptosis-inducing agents.

Full summary

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**Background:** Cell metabolic reprogramming is a hallmark of cancer, and the serine-glycine-one-carbon (SGOC) metabolic network is a critical pathway that supports rapid proliferation. First conceptualized by Mehrmohamadi et al. in 2014, SGOC metabolism provides serine, glycine, and one-carbon units necessary for nucleotide, protein, and lipid biosynthesis, as well as DNA/histone methylation and redox homeostasis. The pathway is particularly co-opted by aggressive cancers, including neuroendocrine prostate cancer, MYCN-amplified neuroblastoma, colorectal cancer, and CDK12-induced breast cancer.

**Methods:** This narrative review synthesizes findings from published literature on SGOC metabolism in cancer, covering key metabolic enzymes (PHGDH, PSAT1, PSPH, SHMT1/2, MTHFD1/2, ALDH1L1/2), transcriptional and epigenetic regulation, roles in cancer immunotherapy and ferroptosis, noncoding RNA interactions, and therapeutic targeting strategies. The authors also reviewed data from genomic analyses, preclinical studies, and clinical trials of SGOC pathway inhibitors.

**Key Results:** PHGDH is the rate-limiting enzyme of serine synthesis; its expression in pancreatic cancer correlates with tumor size, lymph node metastasis, and TNM stage and is an independent prognostic indicator. SHMT1 C1420T polymorphism may be associated with non-Hodgkin's lymphoma risk based on a study of 7,309 patients. In MYC-transformed cells under hypoxia, SHMT2 knockdown reduced the NADPH:NADP+ ratio and triggered hypoxia-induced cell death. Transcriptional regulation of SGOC enzymes involves ATF4, NRF2, MYC, HIF-1/2, and TAZ/YAP. A lysine 64 residue on SHMT2 forms a positive feedback loop with β-catenin/TCF4 in colorectal cancer. In cancer immunotherapy, serine is essential for effector T-cell responses; SLC19A1 is the main transporter for cyclic dinucleotides; and PSAT1 hypermethylation is linked to T-cell dysfunction and shorter survival in breast cancer. MTHFD2 expression in bladder cancer is associated with PD-L1 activation via PI3K/AKT. In ferroptosis, PHGDH binds PCBP2 to stabilize SLC7A11 mRNA and inhibit ferroptosis; c-Jun activates PSAT1 transcription to antagonize erastin-induced ferroptosis in liver cancer. Multiple inhibitors are reviewed: PHGDH inhibitors (BI-4924, CBR-5884, NCT-503, PKUMDL-WQ-2201, azacoccone E, ixocarpalactone A), PSPH inhibitors (clofazimine, CMPSA), SHMT inhibitors (SHIN1, AGF347, compound 2.12), MTHFD inhibitors (LY345899, carolacton), and DHFR/TYMS inhibitors (pemetrexed, methotrexate, 5-FU, trimetrexate, raltitrexed, piritrexim, ZD-9331, GS7904L, ONX-0801). Farletuzumab (anti-FOLR1) and AG-270 (MAT2A inhibitor) are in clinical trials.

**Clinical Implications:** SGOC metabolism represents a targetable vulnerability in highly SGOC-activated tumors. PHGDH inhibition with NCT-503 or shRNA significantly improved the antitumor effect of doxorubicin in triple-negative breast cancer both in vivo and in vitro. Pemetrexed increased T-cell activation in mouse tumors and enhanced anti-tumor effects when combined with PD-1 blockade. Dietary serine/glycine restriction combined with metformin significantly reduced tumor growth rate and final volume in mice. The identification of specific metabolic dependencies may help identify tumor types that would benefit from existing approved therapies. Newer-generation drugs selectively targeting PHGDH, MTHFDs, DHFR, TYMS, GART, and CBS may provide breakthroughs in cancer treatment.