Regulatory T cells (Tregs) are a critical immune component guarding against excessive inflammatory responses, but current understanding of Treg heterogeneity and function in non-lymphoid tissues in humans is limited. In this project we characterized unique types of Treg signatures in the context of tissue-confined inflammatory responses in human skin and gut. During chronic inflammation, Tregs fail to control effector T cell responses. Causes of Treg dysfunction in these diseases are poorly characterized and therapies are aimed at blocking aberrant effector responses rather than rescuing Treg function. We hypothesized that impairment in tissue-specific immune regulation leads to exacerbated T cell responses and chronic inflammation in these diseases. Therefore, we utilized single-cell RNA sequencing data from patients suffering from chronic skin and colon inflammation to show that diseased tissue-Tregs have a strong, specific, tissue-resident signature. We uncover SAT1, the gene encoding spermidine/spermine N1-acetyltransferase (SSAT), as a novel marker and driver of skin-specific Treg dysfunction during TH17-mediated inflammation. Tregs expressing high levels of SAT1 are specifically enriched in chronic skin inflammation and show a proinflammatory effector-like transcriptomic profile. Using CRISPRa in healthy human skin-derived Tregs, we validated that expression of SAT1 leads to loss of suppressive function and a switch to a TH17-like phenotype. This phenotype is induced by co-receptor expression on keratinocytes exposed to a TH17 environment. Lastly, we highlight the potential therapeutic impact of targeting SSAT in a mouse model of skin inflammation by inhibiting SSAT pharmacologically, which rescued Treg number and function in the skin and systemically. Together, our results reveal a novel interface of polyamine catabolism and Treg function in the skin which leads to impaired control of effector T cell responses. Ultimately, our findings significantly contribute to basic understanding of Treg function and shed light on immune regulation during chronic inflammation in human tissue and reveal SSAT as a potential novel target for chronic inflammatory skin disease.