A “Depolarization‐Activation” Strategy Targeting Microglia: Cuproptosis‐Mediated Immune Re‐Sensitization Nanoplatform in Glioma Therapy

ABSTRACT Despite the necessity of repolarizing tumor‐associated microglia/macrophages (TAMs) to reverse the highly immunosuppressive microenvironment in gliomas, clinical translation is hindered by tumor heterogeneity and therapeutic dose safety concerns. Here, we develop a “depolarization‐activation” strategy: cuproptosis depolarizes TAMs to an “erased” stage regardless of tumor subtypes, leading to a universally enhanced susceptibility to immunoactivating agents. The cuproptosis inducer Elesclomol‐Cu (EsCu) and activation agent MK8931 are encapsulated into one nanoplatform with glioma targeting polymers (EsCu/MK@M‐P). Sub‐lethal level cuproptosis treatment significantly downregulates all polarization markers in TAMs, depolarizing TAMs to an immature state. MK8931 at a low dosage subsequently activates TAMs toward a tumor‐killing phenotype, achieving immunotherapeutic efficacy on glioma cells. In vitro and in vivo models, multi‐omics analysis, and patient‐derived organoids validate broad‐spectrum anti‐glioma potency and improved biosafety. Therefore, the “depolarization‐activation” strategy reveals that sub‐lethal hits erase the immunosuppressive property of tumor microenvironment for following immunoactivation, promisingly innovating current cancer immunotherapy strategies.