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

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 (H₂O₂) into oxygen (O₂). 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.