Metabolic Nanoregulators Induce Ferroptosis and Change Metabolite Flow to Reverse Immunosuppressive Tumor Microenvironment
Time：2024/12/18 16:01:25 Views：9
Malignant cells acquire metabolic adaptations that facilitate the utilization of energy and substances for supporting uncontrolled growth while also modulating the immune landscape of the tumor microenvironment (TME). Anti-tumor immune populations that exhibit metabolic antagonism with tumor cells (e.g. CTLs and Teff) are inactivated due to the competition for nutrients with tumor cells or the effects of immunosuppressive metabolites, while immunosuppressive cells (e.g. Tregs) that exhibit metabolic symbiosis with the tumor cells to support tumor cells proliferation through metabolic complementation, ultimately form a drug resistance and immunosuppressive TME. The regulation of metabolic flow in TME is a promising anti-tumor therapy. However, many metabolic regulation drugs lack cell-selective capability and may inadvertently induce unfavorable therapeutic effects. Therefore, improving drug specificity is crucial for achieving safe and effective anti-tumor therapy. The results were published online in ACS NANO (IF=15.8) under the title of Metabolic nanoregulators induce ferroptosis and change metabolite flow to reverse immunosuppressive tumor microenvironment.
The metabolic reprogramming of tumor cells leads to a fixed preference in the metabolic flow of substances within the tumor microenvironment. There are two key features of metabolic reprogramming, one is the bioenergetic shift, known as the “Warburg effect”, which refers to the shift in energy supply from oxidative phosphorylation to glycolysis, enabling mitochondria to supply energy to tumor cells more rapidly. The second is heightened glutamine catabolism, which generates substances such as α-KG, amino acids, and NADPH to meet the uncontrolled growth demands of tumor cells. Exploiting the potential therapeutic opportunities requires simultaneous regulation of abnormal energy and substance metabolism in tumor cells. Ferroptosis, a regulated cell death mode that directly interfere with mitochondria to disrupt energy metabolism, and tumor cells which can escape other form of cell death are still sensitive to ferroptosis. However, most kinds of ferroptosis inducers have demonstrated significant cytotoxic effects on tumor cells in vitro, there has been no success in animal models, with the notable exception of immunodeficient mice. It might be attributed to the detrimental therapeutic effects of ferroptosis on immune cells. A recent study has demonstrated that depletion of cystine induced ferroptosis in pancreatic tumor-bearing mouse models, suggesting that ferroptosis induced by cystine depletion avoids toxicity to immune cells. Regulating mitochondrial energy metabolism alone may be insufficient to control the metabolites flow in TME, emphasizing the critical need to combine other metabolic modulators. Glutamate oxaloacetate transaminase 1 (GOT1) plays a pivotal role in regulating several amino acid metabolic pathways, particularly glutamine metabolism, which is closely related to tumor immunity. GOT1 is dispensable in non-malignant cells but essential to maintain substance supply in tumor cells. Nonetheless, a synthetic lethal relationship between the mitochondrial electron transport chain and GOT1 inhibition is observed, suggesting that GOT1 inhibition may activate of mitochondria-associated metabolic pathways to maintain cellular activity. Screening for targeted metabolic inhibitor library in GOT1 knockdown cells led to the discovery that activation of the ferroptosis-related pathway is vital to kill tumor cells. Therefore, combining cystine depletion to induce ferroptosis and inhibition of GOT1 activity is a promising strategy for synthetic lethal metabolic regulation.
Small-molecule inhibitors have limited clinical application due to their undesirable physicochemical properties, which impact the bioavailability, solubility, and pharmacokinetics of the drugs. Drug delivery strategies have facilitated the translation of promising therapeutics into successful treatments, not only improving the in vivo behaviors of small molecule inhibitors but also enabling simultaneous delivery of multiple drugs within a system. In this study, we selected erastin, which inhibit cystine uptake in tumor cells, and adapalene, which inhibits the enzymatic activity of GOT1, as modulators of tumor cell metabolic reprogramming. The combination of the two drugs can interfere with several metabolic pathways such as redox metabolism, amino acid metabolism and mitochondrial metabolism in tumor cells. Meanwhile, in synergistic therapies, co-delivery of two drugs based on the synergistic index is crucial for maximizing efficacy. Here, we take advantage of the chemical structural features of the adapalene and incorporate it into the delivery system through intracellular-sensitive chemical bonding, thus realizing the on-demand and proportional preparation of the two drugs co-delivery system and avoiding the competitive loading of drugs. Through tumor-targeting peptide modification, the synthetic lethality specificity of the system to tumor cells is further improved, and ultimately enabling precise regulation of metabolites flow within the TME, thus reversing immunosuppression and achieving safe and effective anti-tumor therapy.
Link to the original article: https://pubs.acs.org/doi/10.1021/acsnano.4c13425
