STAT6 Deficiency Accelerates DMBA/TPA-Induced Skin Papilloma Development and Is Associated with Regulatory T-Cell Accumulation and Reduced CD8+IFN-γ+ Responses.

Abstract

Inflammation and the balance between antitumor surveillance and immunoregulatory mechanisms influence chemically induced skin tumor development. STAT6 is a central mediator of IL-4/IL-13 signaling, but its contribution to early skin papilloma development remains unclear. Here, we examined papilloma onset and burden, histopathological alterations, Treg accumulation, and CD8+ T-cell-associated responses in WT and STAT6-deficient mice subjected to a two-stage DMBA/TPA protocol. STAT6-/- mice developed papillomas significantly earlier and exhibited a markedly greater lesion burden than WT mice. This phenotype was associated with more prominent keratinization-related histopathological features, increased Foxp3+ Treg frequency and PD-1 expression in skin-draining lymph nodes, and a broader distribution of Foxp3+ cells within papillomas. STAT6 deficiency was also accompanied by attenuated CD8+IFN-γ+ responses in draining lymph nodes and reduced CD8+ cell infiltration within lesions. Collectively, these findings reveal a distinct immune profile associated with enhanced susceptibility to chemically induced skin papillomas and underscore the context-dependent role of STAT6 in cutaneous tumor immunity.