Ascorbic Acid-Derived Supramolecular Gels Induce Immunogenic Ferroptosis in Cancer Cells to Potentiate Tumor Immunotherapy.

Abstract

High-dose ascorbic acid (AA) therapy induces cancer cell death primarily through its oxidized derivative, dehydroascorbic acid (DHA). However, maintaining therapeutic AA concentrations within tumors and overcoming intratumoral hypoxia pose critical barriers to the clinical application of AA. Herein, we develop an injectable supramolecular gel (αPD-1@Lv/HPAGel) composed of ascorbyl palmitate (an AA derivative), lovastatin-loaded hemoglobin nanoparticles (Lv/Hb-PDA), and the immune checkpoint inhibitor anti-PD-1 (αPD-1). Upon intratumoral administration, this gel system sustains high local AA concentrations and promotes efficient oxidation of AA into DHA by alleviating hypoxia via the release of oxygen from hemoglobin. Simultaneously, lovastatin inhibits glutathione peroxidase 4, synergistically amplifying AA-induced ferroptosis. The coordinated induction of ferroptosis remodels the tumor immune microenvironment and stimulates a robust antitumor immune response. In combination with αPD-1, the gel system suppresses tumor growth and metastasis, establishes durable immune memory, and effectively prevents local and distant tumor recurrence postsurgery. Collectively, these findings present an approach for translating high-dose AA therapy into practice and provide evidence for the integration of ferroptosis induction with immunotherapy for enhanced cancer treatment.