Metabolic Reprogramming of Tumors: Induced Immunosuppression and Therapeutic Prospects of Nanoscale Drug Delivery Systems

The initiation, progression, and metastasis of tumors are accompanied by metabolic reprogramming. Within the tumor immune microenvironment (TIME), the impact of metabolic alterations in tumor cells is often overlooked, leading to therapeutic failure. In reality, tumor cells and immune cells within TIME compete for nutrients, inducing hypoxia, acidosis, and other conditions that collectively foster an immunosuppressive microenvironment. Therapeutic strategies targeting metabolic reprogramming hold great promise for cancer treatment. This account systematically reviews the interplay between tumor metabolic reprogramming and the TIME, focusing on the mechanisms by which metabolic reprogramming mediates immune suppression. It highlights the strategies of nanoscale delivery systems to regulate immune cells through metabolite delivery, including diverse carrier platforms (e.g., liposomes and polymers), active targeting optimization (e.g., ligand-receptor interactions), stimuli-responsive release (e.g., pH/reactive oxygen species (ROS)-triggered systems), and multimodal synergistic therapies (e.g., phototherapy combined with metabolic inhibitors), all aimed at reshaping the metabolic balance between tumor and immune cells. Additionally, the discussion encompasses metabolic reprogramming-driven immune suppression, design strategies for nanoscale systems to reverse immunosuppression via metabolic interventions, and clinical translation. Finally, the application prospects of metabolism-targeted nanodrug delivery systems in tumor therapy are envisioned.