Association of breast cancer subtypes with distinct metabolic phenotypes identified isocitrate dehydrogenase 2 (IDH2) as a key player in triple-negative breast cancer (TNBC) and HER2 subtypes. Wild-type IDH2 promoted cell proliferation, anchorage-independent growth, glycolysis, mitochondrial respiration, and antioxidant defense, thus revealing its protumorigenic role in TNBC cells. Serine biosynthesis pathway proteins were found to be metabolic synthetic dosage lethal partners of IDH2. Pharmacological inhibition of PHGDH sensitized cells with high IDH2 and inhibited tumor growth in vivo, emphasizing PHGDH inhibition as a therapeutic approach for triple-negative breast tumors with high IDH2. For details, see article by Barnabas and colleagues on page 1443.