Dual metabolic checkpoint blockade via a 3D-Printed metalloplatform remodels the tumor ecosystem for systemic antitumor immunity

Abstract

The immunosuppressive tumor microenvironment limits the efficacy of therapies that target metabolism. Here we show a strategy of dual metabolic regulation that simultaneously reprogramming glycolysis in cancer cells and fructose metabolism in tumor-associated macrophages, transforms the metabolic ecosystem from pro-tumor to antitumor, eliciting systemic immunity. Through pan-cancer single-cell analysis, we identified a metabolic division of labor: cancer cells exhibit hyperactive glycolysis, while immunosuppressive macrophages display elevated fructose metabolism. We uncovered that manganese ions (Mn2+) selectively suggest a potential inhibitory effect on glycolysis, induce pyroptosis, yet paradoxically upregulate fructose metabolism in M2-like macrophages, creating an exploitable vulnerability. To harness this dual activity, we engineered a 3D-printed nanoporous Cu-Mn alloy (CuMn) that provides sustained intratumoral release of Mn2+ and delivers a fructokinase inhibitor. In a bilateral breast carcinoma model, a single intratumoral implantation of this platform suppressed primary tumor growth and eradicated distant untreated lesions. Therapeutic efficacy was associated with macrophage reprogramming, which remodeled the immune microenvironment, alleviated T cell exhaustion, and inhibited distant tumor growth, suggesting potential systemic antitumor effects. Local delivery of the nano platform offers a strategy to overcome tumor immunosuppression and enhance cancer immunotherapy.