An ‘AND’ Logic Gate Nanoreactor for Metabolic Remodeling in Starvation‐Ferroptosis‐Immunotherapy of Pancreatic Cancer

Abstract Ferroptosis is an emerging therapeutic strategy in pancreatic cancer (PC) therapy. However, existing ferroptosis often concentrate on the generation of lipid peroxide (LPO), ignoring the negative feedback from intracellular anomalous metabolism, such as lactic acid accumulation. Herein, an “AND” logic gate functional nanoreactor is constructed with a combination of curcumin and glucose oxidase (Gox) (NRs@Cur@Gox) for metabolic remodeling‐mediated starvation, ferroptosis, and immunotherapy. In acidic tumor cells, NRs@Cur@Gox is specifically activated to improve the permeability of the membranes, resulting in increased hydrogen peroxide (H 2 O 2 ) production via the catalysis of Gox. High H 2 O 2 subsequently induces self‐destruction of the nanoreactor, releasing Cur and quinone methides to inhibit the expression of glucose transporter protein 1, generate lactate and deplete glutathione (GSH), respectively. Exhausted intracellular glucose and blockage of extracellular glucose transport interdict tumor cells from the root. Moreover, decreased lactate, increased H 2 O 2 , and GSH depletion synergistically activate ferroptosis. Starvation therapy combined with ferroptosis induces significant immunogenic cell death (ICD), promotes cytotoxic T lymphocyte proliferation, and inhibit PC regression. Importantly, the decreased lactate in the tumor microenvironment reverses immunosuppressive tumors into “hot” tumors, reinforcing the immunotherapeutic efficiency of NRs@Cur@Gox. Overall, this study provides a versatile metabolic intervention strategy for PC‐ferroptosis immunotherapy.