Engineering clinically actionable nanomedicine for cancer immunometabolic ecosystem reprogramming.

Abstract

Traditional metabolic inhibitors have limited clinical efficacy, with issues such as narrow window periods, and compensatory effects. These barriers indicate that effective metabolic therapy requires spatially restricted, temporally coordinated, cell-context-aware, and clinically stratifiable intervention. This review examines how glucose-lactate, lipid-redox, amino acid-immune checkpoint, and nucleotide-adenosine circuits drive tumour progression, immune suppression, and therapeutic escape. We then define the engineering advantages that distinguish nanomedicine from free metabolic drugs, including spatiotemporal control, smart and responsive release, multi-target co-delivery, and organelle targeting. Representative nanomedicine strategies are discussed according to the immunometabolic circuits they modulate, with emphasis on their ability to overcome metabolic compensation, restore immune cell function, and address tumour heterogeneity. Finally, we evaluate key translational challenges, including chemistry, manufacturing and control (CMC), regulatory obstacles, and biomarker selection. This review proposes clinically actionable design principles of nanomedicine for immunometabolic reprogramming.