A Dual-Mechanism Based Nutrient Partitioning Nanoregulator for Enhanced Immunotherapy against Anti-PD-1 Resistant Tumors

Competitive consumption of nutrients between rapidly proliferating cancer cells and T cells results in an immunosuppressive tumor microenvironment (TME) and nutrient deprivation of T cells, which can cause low response rate and resistance to immunotherapies. In this study, we proposed a dual-mechanism based nutrient partitioning nanoregulator (designated as DMNPN), which can simultaneously regulate the immunosuppressive TME and enhance T cell nutrient availability. DMNPN consists of a charge-reversal biodegradable mesoporous silica, encapsulating glycolysis inhibitor lonidamine, and small interfering RNA against glutaminase. Through inhibiting glycolysis to decrease the lactic acid production and downregulating glutaminase expression to reduce the uptake of glutamine by tumor cells, DMNPN enables effective remodeling of metabolism and nutrient partitioning, which alleviates the immunosuppressive TME and boosts nutrient availability for T cells with enhanced antitumor immunity. Such a nutrient partitioning nanoregulator can effectively inhibit the growth of anti-programmed death receptor 1 (anti-PD-1) resistant tumors and prevent tumor metastasis and recurrence. Overall, this dual-mechanism based nutrient reallocation strategy provides a promising approach for cancer therapy.