biostudies-literatureCineus REuropean Research CouncilDeutsche Forschungsgemeinschaft (German Research Foundation)Volkswagen Foundation (VolkswagenStiftung)837-853https://www.ebi.ac.uk/biostudies/studies/S-EPMC12133592biostudies-literatureUnknown26(6)Multicellular cytokine networks drive intestinal inflammation and colitis-associated cancer (CAC). Interleukin-22 (IL-22) exerts both protective and pathogenic effects in the intestine, but the mechanisms that regulate this balance remain unclear. Here, we identify that IL-22 directly induces responsiveness to the IL-6 family cytokine oncostatin M (OSM) in intestinal epithelial cells (IECs) by activating STAT3 and upregulating the OSM receptor. In turn, OSM synergizes with IL-22 to sustain STAT3 activation in IECs and promote proinflammatory epithelial adaptation and immune cell chemotaxis to the inflamed intestine. Conditional deletion of the OSM receptor in IECs protects mice from both colitis and CAC, and pharmacological blockade of OSM attenuates established CAC. Thus, IL-22 and OSM foNature immunologyThe IL-22-oncostatin M axis promotes intestinal inflammation and tumorigenesis.PMC12133592101055309TRR 241-C03 B02 (375876048); RO 3565/7-1TRR 241-A01 (375876048); SFB 1444/P11 (427826188); SPP 1937-DI764/9-2TRR 241-C03 (375876048); GRK 2318-B02 (318905415)101078069MEM-CLONK (101055157)LCAdapt (101055309); GlycanTrigger (101093997)10105515792087Muller NBacher PBojarski CSchurmann SBreart BGunther CConrad TWang LScherl AHainbuch SLopez-Posadas RWest NRTriantafyllopoulou ACancino CAKoop KWirtz SLeppkes MNeufert CKonopka AVelasco Blazquez LMashreghi MFSaliutina MKlose CSNZiai JGuerra GMKeir Mvon Coburg EAbdelrahman ANeurath MKrug SDeigendesch NAtreya ISchumann MSanders ATRR241 IBDome ConsortiumSturzl MRomagnani CDiefenbach ATrajanoski ZGerbeth LAtreya RHildner KHung JCineus RBritzen-Laurent NPruß MRadbruch ASiegmund BManna SHeinrich FLohning MKwon GSchulzke JDWaldner MScheffold ARoels JDurek PRonchi FKuhl AAZundler SBosel DBosch-Voskens CLuo YPatankar JHegazy ANKlementowicz JELudwig LSBecker CChang HDWeidinger CfalseThe IL-22-oncostatin M axis promotes intestinal inflammation and tumorigenesis.Multicellular cytokine networks drive intestinal inflammation and colitis-associated cancer (CAC). Interleukin-22 (IL-22) exerts both protective and pathogenic effects in the intestine, but the mechanisms that regulate this balance remain unclear. Here, we identify that IL-22 directly induces responsiveness to the IL-6 family cytokine oncostatin M (OSM) in intestinal epithelial cells (IECs) by activating STAT3 and upregulating the OSM receptor. In turn, OSM synergizes with IL-22 to sustain STAT3 activation in IECs and promote proinflammatory epithelial adaptation and immune cell chemotaxis to the inflamed intestine. Conditional deletion of the OSM receptor in IECs protects mice from both colitis and CAC, and pharmacological blockade of OSM attenuates established CAC. Thus, IL-22 and OSM fo2025-01-01T00:00:00Z2025 Jun2026-06-02T01:12:06.95Z2026-05-24T03:07:41.87ZS-EPMC121335924044786010.1038/s41590-025-02149-z