SHMT2 is a mitochondrial enzyme that catalyzes serine-to-glycine conversion while producing 5,10-methylenetetrahydrofolate, a critical one-carbon unit donor for cellular metabolism 12. The enzyme serves multiple essential functions: it supports purine and thymidylate biosynthesis 12, enables mitochondrial translation by methylating tRNAs at wobble positions 3, and contributes to oxidative phosphorylation through proper respiratory chain enzyme expression 3. Beyond mitochondrial roles, SHMT2 participates in the BRISC deubiquitination complex, regulating IFNAR1 signaling 1. Clinically, SHMT2 dysregulation drives multiple cancers. In lung adenocarcinoma, MAPK1-mediated phosphorylation at Ser90 stabilizes SHMT2, promoting m6A RNA methylation and oncogene expression 4. Elevated SHMT2 expression associates with poor prognosis in NSCLC through NRF2-dependent upregulation 5 and undifferentiated thyroid cancer 6. SHMT2 amplification initiates lymphoma by inducing epigenetic silencing of tumor suppressors 7. Additionally, SHMT2-driven mitochondrial serine metabolism confers 5-FU chemotherapy resistance in colorectal cancer 8 and supports Burkitt lymphoma survival by maintaining TCF3-dependent BCR signaling 9. These findings position SHMT2 inhibition as a promising therapeutic strategy across multiple malignancies.