Sequential Disruption of Tumor Camouflage and Metabolic Coercion by Cascade-Acting Nano-Proteolysis Targeting Chimera Engines to Reprogram the Immune Ecosystem

Abstract

The clinical efficacy of cancer immunotherapy is fundamentally constrained by the synergistic evasion mechanisms of antigen concealment and effector immune cell suppression. To overcome these barriers, we proposed a therapeutic paradigm that sequentially dismantles the tumor’s “immune camouflage” and relieves “metabolic coercion,” thereby enabling systematic remodeling of the tumor immune microenvironment. A cascade-acting nano-Proteolysis Targeting Chimera (PROTAC) engine was fabricated via phosphatidylcholine-driven self-assembly, enabling tumor-targeted delivery and pH-responsive drug release within the tumor microenvironment. The system initially disrupted the tumor’s immune evasion barrier by inducing cellular senescence and enhancing MHC-I-mediated antigen presentation. It subsequently reprogrammed tumor metabolism through targeted degradation of the BRD4/c-Myc axis, which alleviated nutrient competition and reversed the metabolic suppression of tumor-infiltrating T cells. This sequential intervention potently enhanced dendritic cell activation and antigen-presenting capacity, promoted the infiltration and reactivation of cytotoxic T lymphocytes, and synergistically induced PD-L1 degradation. Collectively, these coordinated effects established a durable antitumor immune response that potently suppressed both primary tumor growth and distant metastasis in a triple-negative breast cancer model. Overall, this work established a cascaded immune remodeling paradigm, conceptualized as unmasking and unblocking, offering a broadly applicable therapeutic strategy to overcome immunosuppression in solid tumors.