The dual role of skin-resident Tregs: balancing autoimmunity in vitiligo and immune evasion in melanoma

Skin-resident regulatory T cells (Tregs) are specialized tissue-resident lymphocytes essential for maintaining skin immune homeostasis and tolerance. However, their functional plasticity allows them to drive diametrically opposing clinical outcomes depending on the local microenvironment. This review comprehensively examines the dual and divergent roles of skin-resident Tregs in two immunologically distinct diseases: vitiligo and melanoma. In vitiligo, an autoimmune condition characterized by the destruction of epidermal melanocytes, quantitative Treg deficiencies, impaired skin homing via the CCL22/CCR4 axis, and phenotypic instability—shifting toward a dysfunctional, pro-inflammatory Th1-like state—precipitate the breakdown of self-tolerance. This permits unrestrained autoreactive CD8+ cytotoxic T cell activity. Conversely, in melanoma, the tumor microenvironment (TME) actively recruits and metabolically reprograms Tregs into a highly suppressive state. These intratumoral Tregs upregulate inhibitory receptors (e.g., TIM-3, PD-1, CTLA-4) and secrete potent immunosuppressive cytokines, facilitating immune evasion by exhausting anti-tumor effector responses. By dissecting the mechanistic parallels and critical differences in Treg trafficking, phenotypic plasticity, and metabolic adaptation, this review provides a unified framework for understanding context-dependent immune regulation. Furthermore, we highlight emerging disease-specific therapeutic strategies, emphasizing approaches to replenish and enhance Treg function to restore immune tolerance in vitiligo, while selectively depleting or functionally impairing intratumoral Tregs to unleash anti-tumor immunity in melanoma.