Targeted PD-L1 degradation with an injectable hydrogel reverses chemotherapy-induced compensatory immunosuppression and enhances antitumor immunity

ABSTRACT Chemotherapy frequently induces compensatory PD-L1 upregulation in tumor cells. This adaptive response limits the durability of immune checkpoint blockade and contributes to therapeutic resistance. To overcome this barrier, we engineered an injectable hydrogel system (G-DMNP/Met) for sustained, localized PD-L1 degradation. The hydrogel continuously releases PEGylated doxorubicin-Mn 2+ chelate nanoparticles (DMNP) and metformin (Met) within the tumor microenvironment. This design enforces persistent depletion of PD-L1 and sensitizes tumors to chemo-immunotherapy. Unlike antibody-based PD-1/PD-L1 blockade, which transiently interrupts receptor-ligand engagement, our strategy directly reduces total PD-L1 protein levels. Continuous degradation prevents chemotherapy-induced PD-L1 rebound and reverses compensatory immune tolerance at its source. Local released DMNP induces immunogenic cell death and activates the cGAS-STING pathway via Mn 2+ -mediated signaling. This process enhances interferon-gamma (IFN-γ) production and restores cytotoxic T lymphocyte priming and effector function. Concurrently, sustained Met release further accelerates PD-L1 degradation, alleviates post-chemotherapy immunosuppression, and promotes effector T-cell infiltration. In vivo, this triple-synergistic approach, PD-L1 degradation, immunogenic cell death induction, and cGAS-STING activation, robustly amplifies antitumor immunity and effectively suppresses immune-cold colorectal tumors under chemotherapeutic conditions. This work presented a protein degradation-driven chemo-immunotherapy paradigm that overcomes chemotherapy-induced adaptive immune resistance and potentiates durable therapeutic responses.