Immunotherapy has emerged as a milestone antitumor technique that eradicates tumor cells by harnessing the immune system to provoke a sturdy immune response [1], [2], [3]. Nonetheless, a big subset of sufferers with malignant tumors typically expertise poor remedy efficacy resulting from immune evasion brought on by the immunosuppressive tumor microenvironment (TME) [4]. It’s predominantly created by extremely proliferating tumor cells competing for vitamins with immune cells by metabolic reprogramming [5], primarily characterised by cardio glycolysis and glutamine habit [6], [7]. Because the proposal of the “Warburg impact”, methods to enhance immunotherapy by modulating glycolysis have attracted widespread consideration, whereas glutamine habit, as a metabolic pathway with even fiercer competitors, has remained on the margins of analysis [8], [9]. Notably, current insights have revealed that immunosuppressive M2-type tumor-related macrophages (TAMs) reveal a higher dependency on glutamine metabolism in comparison with M1-type TAMs. To be extra particular, glutaminolysis-derived alpha-Ketoglutaric acid (α-KG) might facilitate the M2-type activation of TAMs, thereby selling tumor development and metastasis by boosting fatty acid oxidation and inducing Jmjd3-dependent epigenetic reprogramming of M2-related genes [10]. What’s extra, glutamine metabolism markedly inhibits CD8+ T cell activation, consequently leading to inadequate activation of endogenous antitumor immunity [11]. Due to this fact, modulating immunotherapy by concentrating on glutamine metabolism might turn into a promising technique for most cancers remedy.
Ferroptosis, an iron-dependent type of regulated cell loss of life, is able to inducing mobile lipid peroxidation [12], [13]. However, its efficacy is inhibited by the antioxidant protection system that’s created by the irregular metabolic panorama in malignant tumors. Specifically, glutamine may very well be damaged down by glutaminase (GLS) to glutamate [14], which serves as a substrate for the biosynthesis of lipids and glutathione (GSH), taking part in indispensable roles in sustaining intracellular redox stability and fueling tumor power whereas additionally notably impacting the therapeutic efficacy of ferroptosis [15], [16]. Moreover, ferroptosis can set off ICD of tumor cells to launch damage-associated molecular patterns (DAMPs) for the stimulation of dendritic cell (DC) maturation and T cell infiltration, thus enhancing the efficacy of antitumor immune responses [17]. Accordingly, the rational modulation of glutamine metabolism is predicted to concurrently improve ferroptosis and reverse immunosuppressive results, attaining a cascade enhancement of immune efficacy.
Because the important nutrient metallic ion, Mn2+ performs an indispensable position in immune processes [18], notably in modulating each innate immune sensing and the host protection towards invading pathogens [19], [20]. Mechanistically, Mn2+ can potentiate cyclic GMP-AMP synthase (cGAS) activation and sensitivity to tumor-derived cytosolic double-stranded DNA (dsDNA) as an immune agonist [21], [22], activating the cyclic GMP-AMP synthase-stimulator of the interferon genes (cGAS-STING) pathway to induce the discharge of downstream sort I interferon (IFN) and thus set off a sturdy innate immune response [23]. Nonetheless, the current investigations on innate immunity are nonetheless within the preliminary stage and have all the time centered totally on the impact of Mn2+ on the cGAS-STING pathway by decreasing the brink for cGAS activation, ignoring the direct impression of elevated dsDNA [24], [25]. To the most effective of our data, there have been few reviews combining ferroptosis with efficient dsDNA era.
Herein, we assemble a self-assembled bimetallic immunoadjuvant (designated as FMSD) of Fe and Mn ions because the metallic connecting factors with natural ligands, additional loaded with the glutamine antagonist diazooxonorleucine (DON) (Scheme 1). Because of the existence of disulfide bonds (S-S) in ligands, it may GSH-responsively launch multivalent metallic ions after cell internalization, inducing intense intracellular lipid peroxidation and ferroptosis, which triggers ICD and enhances immunogenicity. Subsequently, with the incidence of ferroptosis mediated by the ROS storm, dsDNA generated from broken mitochondria and deceased cell particles was transformed into the immune-enhancing agent whereas synergistically with Mn2+ stimulating the cGAS-STING pathway, thus activating innate immunity. Moreover, the launched DON not solely successfully inhibits the glutamine metabolism of tumors, facilitates the polarization of macrophages in the direction of the pro-inflammatory M1-type, and restores the perform of T cells [26], but additionally disrupts redox stability of tumor cells to dam the synthesis of GSH, additional enhancing ferroptosis and boosting immunotherapy efficacy [27]. Collectively, this cascade enhancement technique for a number of regulation reveals an observable inhibitory impact on main tumor development, in addition to metastasis to distal tumors and lungs, offering beneficial insights for immunotherapy by combining innate immunity with amino acid metabolism.
