Mitoxantrone‐Encapsulated ZIF‐8 Enhances Chemo‐Immunotherapy via Amplified Immunogenic Cell Death

Abstract Chemo‐immunotherapy, combining systemic chemotherapeutic drugs and immune checkpoint blockers, is a promising paradigm in cancer treatment. However, challenges such as limited induction of immune responses and systemic immune toxicity have hindered its clinical applications. Here, a zeolite imidazolate framework‐8 (ZIF‐8) that encapsulates mitoxantrone (MIT), an immune cell death (ICD)‐inducing chemotherapeutic agent (MIT@ZIF‐8), is synthesized using a one‐pot aqueous‐phase process. ZIF‐8 serves as a dual‐functional nanomaterial for chemo‐immunotherapy: a carrier to enhance tumor uptake of MIT for improved chemotherapy efficacy, and a pyroptosis inducer to amplify MIT‐induced ICD for augmented anti‐tumor immune responses. As a result, in vivo administration of MIT@ZIF‐8 markedly inhibits tumor growth in both immunologically “hot” colon cancer and immunologically “cold” prostate cancer. Moreover, MIT@ZIF‐8 treatment increases the abundance of cytotoxic CD8 + T cells and reduces the amount of immunosuppressive regulatory T cells in tumors, thereby enhancing anti‐tumor immunity and sensitizing prostate cancer to anti‐CTLA‐4 immunotherapy. In summary, MIT@ZIF‐8 offers a highly translational approach for chemo‐immunotherapy.