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Fumarate is an oncometabolite. However, the mechanism underlying fumarate-exerted tumorigenesis remains unclear. Here, utilizing human type2 papillary renal cell carcinoma (PRCC2) as a model, we show that fumarate accumulates in cells deficient in fumarate hydratase (FH) and inhibits PTEN to activate PI3K/AKT signaling. Mechanistically, fumarate directly reacts with PTEN at cysteine 211 (C211) to form S-(2-succino)-cysteine. Succinated C211 occludes tethering of PTEN with the cellular membrane, thereby diminishing its inhibitory effect on the PI3K/AKT pathway. Functionally, re-expressing wild-type FH or PTEN C211S phenocopies an AKT inhibitor in suppressing tumor growth and sensitizing PRCC2 to sunitinib. Analysis of clinical specimens indicates that PTEN C211 succination levels are positively correlated with AKT activation in PRCC2. Collectively, these findings elucidate a non-metabolic, oncogenic role of fumarate in PRCC2 via direct post-translational modification of PTEN and further reveal potential stratification strategies for patients with FH loss by combinatorial AKTi and sunitinib therapy. [Display omitted] • Fumarate directly targets and succinates PTEN at C211 • C211 succination abrogates the interaction of PTEN with the cellular membrane • PTEN C211 succination is positively correlated with PI3K/AKT activation in PRCC2 • Inhibiting PTEN C211 succination or AKT sensitizes PRCC2 to sunitinib treatment Ge et al. report that fumarate, an oncometabolite, succinates PTEN at C211, which abrogates the binding of PTEN with the cellular membrane. C211 succination of PTEN thereby activates PI3K/AKT signaling and promotes tumor growth of PRCC2. Inhibiting PTEN C211 succination or AKT activation enhances sensitivity of PRCC2 to sunitinib treatment. [ABSTRACT FROM AUTHOR]