Engineering Dual‐Responsive Prodrug‐MOFs as Immunogenic Cell Death Initiator for Enhancing Cancer Immunotherapy

Abstract In recent years, the anticancer effects of disulfiram, a clinical drug for anti‐alcoholism, are confirmed. However, several defects limit the clinical translation of disulfiram obviously, such as Cu(II)‐dependent anticancer activity, instability, and non‐selectivity for cancer cells. Herein, a phosphate and hydrogen peroxide dual‐responsive nanoplatform (PCu‐HA‐DQ) is reported, which is constructed by encapsulating disulfiram prodrug (DQ) and modifying hyaluronic acid (HA) on copper doping metal–organic frameworks (PCu MOFs). PCu‐HA‐DQ is expected to accumulate in tumor by targeting CD‐44 receptors and enable guidance with magnetic resonance imaging. Inside the tumor, Cu(DTC) 2 will be generated in situ based on a dual‐responsive reaction. In detail, the high concentration of phosphate can induce the release of DQ, after that, the intracellular hydrogen peroxide will further mediate the generation of Cu(DTC) 2 . In vitro and in vivo results indicate PCu‐HA‐DQ can induce the apoptosis as well as immunogenic cell death (ICD) of tumor cells distinctly, leading to enhanced immune checkpoint inhibitor (ICI) efficacy by combining the anti‐programmed death‐1 antibody. This work provides a portable strategy to construct a dual‐responsive nanoplatform integrating tumor‐targeted ability and multi‐therapy, and the designed nanoplatform is also an ICD inducer, which presents a prospect for boosting systemic antitumor immunity and ICI efficacy.