Oxygen Delivery Reprograms Hypoxic Tumor Niche to Rejuvenate CAR-NKT Cells for Improved Cancer Immunotherapy

Adoptive cell therapies have revolutionized the treatment of hematologic malignancies, but their success in solid tumors remains limited. Chimeric antigen receptor (CAR)-engineered invariant natural killer T (CAR-NKT) cells represent a promising frontier in immunotherapy, combining innate immune properties with engineered specificity against cancer. Despite their potential, the therapeutic efficacy of CAR lymphocytes is often compromised by tumor hypoxia. A hallmark of solid tumors, hypoxia reprograms immune cell metabolism, promotes immunosuppression, drives exhaustion and impairs cytotoxicity. To address this, we introduce Hypoxia-attenuating Oxygenating Platform for Enhanced-Immunotherapy (HOPE), an oxygen delivering modular platform that alleviates hypoxic tumor microenvironment and enhances CAR-NKT cell functionality in vivo . Using in vitro hypoxia model, we demonstrate how HOPE reverses hypoxia-induced suppression, restores mitochondrial membrane potential, synergizes CAR-NKT cell functionality, and reduces immune exhaustion. Furthermore, in vivo xenograft solid tumor model shows that HOPE increases intratumoral CAR-NKT persistence and significantly reduces tumor burden. Together, these results establish HOPE as a translatable immunoengineering strategy that rejuvenates CAR-NKT activation, metabolism and checkpoint phenotype and improves antitumor efficacy in hypoxic solid tumors, which has broad potential as an enabling platform for next-generation adoptive cell therapies.