IL-36γ Drives Th9 cell Differentiation via IκBζ to Sustain Antitumor Immunity

Abstract

Th9/Tc9 cells polarized with TGF-{beta} and IL-4 exhibit superior antitumor efficacy, prompting extensive efforts to optimize their differentiation protocols and augment therapeutic potency. In the current study, we identified IL-36{gamma} as a potent cytokine that synergizes with TGF-{beta} to robustly drive Th9 differentiation both in the presence and absence of IL-4. IL-36{gamma}-programmed Th9 cell subsets exhibited phenotypic and transcriptional profiles identical to classic Th9 cells. Mechanistically, IL-36{gamma} drove Th9 cell differentiation through amplifying key signaling pathways such as STAT6, STAT5, and NF-{kappa}B that are essential for classic Th9 programming. Notably, we uncovered a novel regulatory axis wherein IL-36{gamma} upregulates the transactivation factor I{kappa}B{zeta}, which directly governs Th9 lineage specification. In in adoptive cell therapy (ACT) models, IL-36{gamma}-polarized Th9 cell subsets demonstrated enhanced antitumor efficacy, attributable to their sustained persistence, reduced exhaustion markers and stem-like/memory properties. Collectively, this study elucidates a previously unrecognized I{kappa}B{zeta}-dependent mechanism underpinning Th9 differentiation and highlights the translational potential of IL-36{gamma}-engineered Th9 cells as a valuable ACT strategy for refractory tumors.