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

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.