CD4+ T-Cells Drive Triple Negative Breast Cancer Recurrence via Non-Canonical TGFβ Signaling

Abstract Radiation therapy is a cornerstone of breast cancer treatment and reduces recurrence overall. However, patients with triple negative breast cancer (TNBC) continue to experience recurrence at higher rates than patients with other subtypes, especially when immunocompromised. While CD8⁺ T-cells are known to mitigate recurrence, the role of CD4+ T-cell subsets in shaping the irradiated microenvironment remains unclear. We show that irradiated mammary tissue from mice accumulates CD4+ T-cells and exhibits a TGFβ-enriched cytokine milieu coincident with macrophage infiltration. We demonstrate that Th2-polarized CD4+ T-cells promote invasion of TNBC cells and macrophages through secretion of TGFβ. Neutralization of TGFβ significantly reduces this invasive phenotype. Mechanistically, Th2-conditioned media induces Tgfb1 expression in both TNBC cells and macrophages, establishing a TGFβ-dependent feed-forward amplification loop. In TNBC cells, Th2-derived TGFβ activates non-canonical signaling characterized by increased p38 MAPK and NF-κB phosphorylation, linking cytokine exposure to pro-invasive behavior. Together, these findings identify Th2-derived TGFβ as a driver of pro-invasive tumor reprogramming and suggest that interruption of Th2–TGFβ signaling may prevent recurrence following therapy.