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.