Size‐Transformable Supramolecular Nanoprodrugs Enable Redox Imbalance Amplification and Cholesterol Modulation to Boost Multidimensional Tumor Immunotherapy

ABSTRACT Low immunogenicity and highly immunosuppressive tumor microenvironment (TME) present major challenges in immunotherapy, as they restrict T lymphocyte infiltration and activation. Although ferroptosis induction has emerged as a promising approach for enhancing tumor immunogenicity and promoting T cell recruitment, its efficacy is frequently compromised by cholesterol‐driven T cell functional exhaustion. To address these limitations, we engineered tumor‐targeting, TME‐responsive, and size‐switchable supramolecular nanoprodrugs that enable multidimensional immune activation. Nanoprodrugs orchestrate a sophisticated cascade of immune activation through four synergistic mechanisms: 1) size‐switchable disassembly upon glutathione/ cholesterol exposure for deep tumor penetration; 2) redox imbalance driven by reactive nitrogen species accumulation and glutathione depletion via the synergistic action of oxaliplatin, ferrocene, and RRx‐001 for ferroptosis augmentation; 3) immunogenic cell death induction via ferroptosis‐apoptosis to initiate tumor immunity cycle, promoting T cell infiltration; and 4) T cell function reinvigoration with the downregulation of programmed cell death protein 1 and T‐cell immunoglobulin 3 expression through cholesterol depletion in TME. This integrated approach achieved primary and distant tumor growth suppression, established durable immune memory against recurrence, and systemically enhanced the antitumor immunity. By concurrently targeting tumor immunogenicity, TME immunosuppression, and T cell exhaustion, this multidimensional strategy represents a transformative advancement in cancer immunotherapy.