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.