Biomimetic Nanomedicine for Senescence‐Modulated Immune Activation Enhances Immunotherapy Efficacy in Hepatocellular Carcinoma

Abstract Tumor senescence, a double‐edged sword, can suppress tumor growth but also promote immune evasion if not properly cleared. Herein, a cell membrane‐coated ZIF‐8@MnOx nanoplatform co‐loaded with doxorubicin (DOX) and piperlongumine (PL), termed mPDZM, is developed to remodel the senescence‐mediated immune response in hepatocellular carcinoma. PL synergizes with DOX to amplify intracellular oxidative stress, which promotes both the killing of tumor cells and the clearance of senescent cells. The biomimetic ZIF‐8@MnOx nanoplatform potentiates the efficacy of DOX and PL by integrating targeted delivery, hypoxia relief, and redox homeostasis disruption. mPDZM remodels the immunosuppressive microenvironment by regulating SASP release, inducing immunogenic cell death, and activating the STING signaling pathway. In vivo, mPDZM exhibits preferential tumor accumulation and minimal systemic toxicity. mPDZM treatment leads to significant tumor suppression both in the senescent and non‐senescent tumor models. Moreover, mPDZM effectively promotes CD8 + T cell and NK cell infiltration, while reducing immunosuppressive Treg cells and M2‐like macrophages. In combination with anti‐PD‐L1 therapy, mPDZM further potentiates antitumor immunity and induces a robust abscopal effect against distant tumors. Collectively, these findings unveil a new paradigm that integrates senescence modulation with immune activation via a biomimetic nanotherapeutic platform and offers a promising combinatorial approach to overcome immune resistance in solid tumors.