Autophagy-Targeting Fe-Cu Nanozyme for Tumor Immune Microenvironment Remodeling and Image-Guided Cancer Immunotherapy.

Abstract

The suppressive tumor immune microenvironment (TIME) is a critical driver of tumor progression, immune evasion, and therapy resistance. Despite the transformative potential of immunotherapy, autophagy within the TIME weakens immune surveillance by downregulating tumor cell surface major histocompatibility complex class I (MHC-I) expression, thereby facilitating immune escape. Here, a novel nanozyme-based strategy is reported to modulate autophagy and restore anti-tumor immunity. Iron-copper metal-organic frameworks (Fe-Cu MOFs) are engineered with tunable peroxidase, glutathione peroxidase, and oxidase-like activities, and an optimal Fe:Cu ratio that confers potent redox activity alongside robust inhibition of autophagic flux is identified. These MOF nanozymes selectively impair autophagy and restore MHC-I expression in tumor cells, enhancing immune recognition. To further potentiate autophagic blockade, a multifunctional nanoplatform (FCMP@CQ/PFH) is developed by co-loading low-dose chloroquine (CQ) and encapsulating perfluorohexane (PFH) into the Fe-Cu MOFs. This combinatorial system couples nanozyme-driven redox stress with lysosomal inhibition to synergistically suppress autophagy and reinvigorate anti-tumor immune responses. Moreover, PFH facilitates ultrasound-based real-time visualization of therapeutic efficacy. Both in vitro and in vivo studies show that FCMP@CQ/PFH enhances cancer immunotherapy and suppresses metastasis. This study establishes a dual-functional approach that combines autophagy inhibition with immune microenvironment reprogramming to circumvent immune resistance and advance precision cancer immunotherapy.