IL-36γ Drives Th9 cell Differentiation via IκBζ to Sustain Antitumor Immunity in Adoptive Cell Therapy

Th9/Tc9 cells polarized with TGF-β 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-36γ as a potent cytokine that synergizes with TGF-β to robustly drive Th9 differentiation both in the presence and absence of IL-4. IL-36γ-programmed Th9 cell subsets exhibited phenotypic and transcriptional profiles identical to classic Th9 cells. Mechanistically, IL-36γ drove Th9 cell differentiation through amplifying key signaling pathways such as STAT6, STAT5, and NF-κB that are essential for classic Th9 programming. Notably, we uncovered a novel regulatory axis wherein IL-36γ upregulates the transactivation factor IκBζ, which directly governs Th9 lineage specification. In in adoptive cell therapy (ACT) models, IL-36γ-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 IκBζ-dependent mechanism underpinning Th9 differentiation and highlights the translational potential of IL-36γ-engineered Th9 cells as a valuable ACT strategy for refractory tumors.