Supramolecular‐Engineered Immune Modulator Orchestrates Tumor Microenvironment Reprogramming for Antibody‐Independent Radio‐Immunotherapy

Abstract Cancer immunotherapy has revolutionized oncological treatment by harnessing the immune system to target and eliminate malignant cells, with radiotherapy (RT) distinguished among immune‐activating strategies for its potent ability to trigger immunogenic cell death (ICD). However, the antitumor immune responses by RT‐mediated ICD are frequently hindered by the RT resistance and immunosuppressive tumor microenvironment (TME), particularly sustained hypoxia and cytoprotective autophagy. Herein, a supramolecular immune modulator based on sulfonated azocalix[4]arene (SAC4A)‐engineered natural catalase (CAT) with hydroxychloroquine (HCQ) encapsulation to potentiate antibody‐independent radio‐immunotherapy by reprogramming TME is developed. This designed modulator can alleviate tumor hypoxic microenvironment and overcome hypoxia‐induced RT resistance by converting tumor endogenous hydrogen peroxide (H 2 O 2 ) into oxygen (O 2 ). Simultaneously, the released HCQ from SAC4A‐engineered CAT under the catalysis of tumor‐overexpressed azo reductase can disrupt the autophagy process, further reprogramming the immunosuppressive TME and amplifying the RT‐induced ICD effect. As a result, treatment with this supramolecular‐engineered immune modulator can significantly enhance the therapeutic efficacy of RT against 4T1 tumor by evoking robust antitumor immune responses, including promotion of dendritic cells maturation, cytotoxic T lymphocytes infiltration, and M1‐like macrophages repolarization. Therefore, this work provides a simple and efficient supramolecular engineering strategy to modulate TME and enhance radio‐immunotherapy, greatly promising for clinical translation.