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Post-translational redox modification of cysteine residues has emerged as an important mode of immune cell regulation, particularly in macrophage cytokine responses. Here, we develop a strategy for systematic discovery and small-molecule functionalization of redox-regulated cysteines on immunological proteins. Using deep redox proteomics, we annotate 788 in vivo redox-regulated cysteines across diverse immune-relevant protein domains. We demonstrate how these sites enable cysteine-directed pharmacology through discovery of a novel cysteine activation site on the immune regulator SHP1. Targeting Cys102, we develop a highly selective covalent agonist, SCA, which binds the N-SH2 domain to relieve autoinhibition and activate SHP1. In mouse and human macrophages, SCA selectively engages SHP1 Cys102, antagonizing IRAK signaling and LPS-induced pro-inflammatory cytokine production. Together, this work identifies a druggable cysteine redox switch controlling macrophage cytokine responses and provides a compendium of redox-regulated sites for therapeutic development.<\/jats:p>","DOI":"10.64898\/2026.02.19.706790","type":"posted-content","created":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T15:20:16Z","timestamp":1771600816000},"source":"Crossref","is-referenced-by-count":0,"title":["A druggable redox switch on SHP1 controls macrophage inflammation"],"prefix":"10.64898","author":[{"given":"Mei Ying","family":"Ng","sequence":"first","affiliation":[{"name":"Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA"},{"name":"Department of Cell Biology, Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-0501-8452","authenticated-orcid":false,"given":"Meredith N.","family":"Nix","sequence":"additional","affiliation":[{"name":"Department of Chemical and Systems 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