FLT3LG induction by γ-chain cytokine promotes regulatory-like CD4+ T cell features in breast cancer

Regulatory and dysfunctional CD4 + T cell states contribute to immune evasion in breast cancer (BC), but the molecular programs associated with these phenotypes remain incompletely understood. Here, we identify FLT3 ligand (FLT3LG) as a γ-chain (γc) cytokine-responsive factor enriched in CD4 + T cells of BC. Public transcriptomic and scRNA-seq analyses showed that FLT3LG expression was linked to Treg-enriched immune regulatory signatures. In Jurkat T cells, FLT3LG overexpression (OE) increased regulatory markers and inhibitory receptors while reducing effector cytokine expression and proliferative capacity, consistent with a regulatory-like and reduced effector phenotype rather than bona fide Treg differentiation. In BC co-culture models, HER2 + BC cell lines induced FLT3LG and FOXP3 expression in Jurkat and primary human T cells. FLT3LG-OE T cells were further associated with increased Ki-67 expression and reduced apoptosis in co-cultured BC cells, as well as altered CFSE profiles of primary responder T cells. Mechanistically, γc cytokines induced FLT3LG expression through STAT5-dependent signaling. In a syngeneic mammary tumor model, FLT3LG expression increased in CD4 + T cells during tumor progression, particularly within the Treg subset. Consistently, clinical dataset analyses showed that high FLT3LG expression was associated with poor outcomes in HER2 + and highly proliferative BC contexts. Together, these findings reveal a γc cytokine-STAT5-FLT3LG regulatory circuit linked to CD4 + T cell immunoregulation in BC.