We show that (a) IL‐22 is specifically upregulated in the TME during the malignant transition stage of tumor progression; (b) IL‐22 expression correlates with aggressive phenotype in breast cancer; (c) disruption of IL‐22 gene specifically inhibits malignant transition stage; and (d) IL‐22 supplementation reinstates breast cancer malignancy in IL‐22 knockout mice. The gene discussed is IL22; the disease is breast cancer.