Bimetallic nanoadjuvant-mediated glutamine metabolism intervention and STING activation for enhanced antitumor immunity

Immune evasion induced by tumor metabolic reprogramming and the low immunogenicity of tumors resulting in insufficient antitumor immune responses have severely hindered the efficacy of immunotherapy. Herein, we design a bimetallic immunoadjuvant with infinite coordination based on Fe and Mn ions as metal connection points, loaded with the glutamine antagonist diazooxonorleucine (DON), to initiate a robust systemic immune response by targeting glutamine metabolism and activating the stimulator of interferon genes (STING) pathway. The nanoadjuvant exhibits stronger capabilities for generating hydroxyl radicals and depleting glutathione, effectively inducing ferroptosis and immunogenic cell death (ICD). Ingeniously, remarkable ferroptosis amplifies oxidative stress and promotes the generation and cytoplasmic leakage of dsDNA, which acts as an immune-enhancing agent synergistically with Mn²⁺ to trigger the cGAS-STING innate immune pathway. Moreover, this nanoadjuvant can inhibit glutamine metabolism, thereby reversing the immunosuppressive microenvironment and restoring immune cell function while disrupting the redox homeostasis and energy supply of tumor cells, which further sensitizes ferroptosis. Overall, this cascade-enhanced immunotherapy strategy achieves a broader spectrum of immunotherapy by closely combining innate and adaptive immunity via the intervention of glutamine metabolism and ferroptosis. This study facilitates the progress of amino acid metabolism regulation-based cancer therapy and offers a promising treatment strategy for enhancing antitumor immunity.