As　a　rising　generation　of　nanozymes,　single　atom　enzymes　show　significant　promise　for　cancer　therapy,　due　to　their　maximum　atom　utilization　efficiency　and　well-defined　electronic　structures.　However,　it　remains　a　tremendous　challenge　to　precisely　produce　a　heteroatom-doped　single　atom　enzyme　with　an　expected　coordination　environment.　Herein,　we　develop　an　anion　exchange　strategy　for　precisely　controlled　production　of　an　edge-rich　sulfur　(S)-and　nitrogen　(N)-decorated　nickel　single　atom　enzyme　(S-N/Ni　PSAE).　In　particular,　sulfurized　S-N/Ni　PSAE　exhibits　stronger　peroxidase-like　and　glutathione　oxidase-like　activities　than　the　nitrogen-monodoped　nickel　single　atom　enzyme,　which　is　attributed　to　the　vacancies　and　defective　sites　of　sulfurized　nitrogen　atoms.　Moreover,　both　in　vitro　and　in　vivo　results　demonstrate　that,　compared　with　nitrogen-monodoped　N/Ni　PSAE,　sulfurized　S-N/Ni　PSAE　more　effectively　triggers　ferroptosis　of　tumor　cells　via　inactivating　glutathione　peroxidase　4　and　inducing　lipid　peroxidation.　This　study　highlights　the　enhanced　catalytic　efficacy　of　a　polynary　heteroatom-doped　single　atom　enzyme　for　ferroptosis-based　cancer　therapy.