Biomineralized MnO₂ Nanoplatforms Mediated Delivery of Immune Checkpoint Inhibitors with STING Pathway Activation to Potentiate Cancer Radio-Immunotherapy

Radiotherapy (RT), as one of the main methods in the clinical treatment of various malignant tumors, would induce systemic immunotherapeutic effects by triggering immunogenic cell death (ICD) of cancer cells. However, the antitumor immune responses produced by RT-induced ICD alone usually are not robust enough to eliminate distant tumors and thus ineffective against cancer metastases. Herein, a biomimetic mineralization method for facile synthesis of MnO2 nanoparticles with high anti-programmed death ligand 1 (alpha PDL1) encapsulation efficiency (alpha PDL1@MnO2) is proposed to reinforce RT-induced systemic antitumor immune responses. This therapeutic nanoplatforms-mediated RT can significantly improve the killing of tumor cells and effectively evoke ICD by overcoming hypoxia-induced radio-resistance and reprogramming the immunosuppressive tumor microenvironment (TME). Furthermore, the released Mn2+ ions from alpha PDL1@MnO2 under acidic tumor pH can activate the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway and facilitate the dendritic cells (DCs) maturation. Meanwhile, alpha PDL1 released from alpha PDL1@MnO2 nanoparticles would further promote the intratumoral infiltration of cytotoxic T lymphocytes (CTLs) and trigger systemic antitumor responses, resulting in a strong abscopal effect to effectively inhibit tumor metastases. Overall, the biomineralized MnO2-based nanoplatforms offer a simple strategy for TME modulation and immune activation, which are promising for enhanced RT immunotherapy.