A Self-Amplifying MOF Nanoplatform for Cancer Immunotherapy Synergizing Starvation-Enhanced Cuproptosis and cGAS–STING Activation

Cancer immunotherapy has emerged as a revolutionary approach that harnesses both innate and adaptive immune systems to combat tumors. However, the limited clinical response rates underscore the urgent need for strategies to enhance therapeutic efficacy. Metal ions such as copper (Cu) and manganese (Mn) have garnered increasing attention due to their roles in immune modulation and induction of cancer cell death. Cuproptosis, a recently identified form of programmed cell death triggered by intracellular Cu overload, disrupts mitochondrial respiration, thereby inducing immunogenic cell death and activating the cGAS-STING pathway via mitochondrial DNA (mtDNA) release. However, cancer cells that rely on glycolysis are less sensitive to cuproptosis than those dependent on mitochondrial respiration, prompting efforts to enhance cuproptosis by inhibiting glycolysis. Glucose oxidase (GOx)-mediated glucose depletion offers a promising metabolic strategy but is hampered by tumor hypoxia and the accumulation of hydrogen peroxide (H2O2) and gluconic acid. To overcome these limitations, we developed a multifunctional nanoplatform, Cu-MOF@MnO2/GOx (CMG), designed to achieve self-amplifying glucose oxidation, which leads to starvation-enhanced cuproptosis and synergistic cGAS-STING activation for enhanced cancer immunotherapy. In this system, GOx depletes glucose to reprogram tumor metabolism and enhance cuproptosis sensitivity, while MnO2 alleviates hypoxia by scavenges harmful byproducts and generates O2 in situ. Additionally, Mn ions activate the cGAS-STING pathway, which is further amplified by cuproptosis-induced mtDNA release. This collaborative strategy effectively stimulates both innate and adaptive immune responses, significantly boosting the therapeutic performance of αPD-L1 immunotherapy. The CMG nanoplatform offers a promising strategy to intensify immunotherapy by targeting metabolic vulnerabilities and immune modulation, representing a promising strategy for next-generation cancer treatment.