Ex Vivo Zinc Nanoparticle Conditioning Primes T Cells for Potent Antitumor Activity in Ovarian Cancer Patient-Derived Xenografts.

T-cell dysfunction imposed by the tumor microenvironment limits the durability of cellular immunotherapies, motivating interventions that strengthen effector programs before infusion. Here we describe an ex vivo pretreatment that uses zinc nanoparticles (Zn NPs) as a transient intracellular Zn2+ modulator to condition T cells without altering receptor engineering. Brief priming with Zn NPs yielded T cells with consistently improved tumor-cell killing across effector-to-target ratios and increased IL-2, IFN-γ, and TNF-α secretion while avoiding rises in intracellular ROS. In murine melanoma models, adoptive transfer of primed T cells delayed tumor growth and prolonged survival without toxicity; combination with Galectin-9 blockade further enhanced control. Translational relevance was supported in an ovarian cancer patient-derived xenograft model, where primed CAR T cells achieved superior tumor control, showed greater intratumoral CAR T infiltration, and again benefited from Galectin-9 inhibition. Transcriptome profiling of primed T cells revealed coordinated remodeling of metal-ion response, consistent with reinforced signaling and stress resilience. This study establishes Zn NP-enabled priming as a practical, drop-in step for T-cell manufacturing that enhances effector function and cooperates with galectin-axis inhibition to overcome microenvironmental suppression and improve therapeutic potency.