The RNA m6A writer METTL3 in tumor microenvironment: emerging roles and therapeutic implications.

The tumor microenvironment (TME) is a heterogeneous ecosystem comprising cancer cells, immune cells, stromal cells, and various non-cellular components, all of which play critical roles in controlling tumor progression and response to immunotherapies. Methyltransferase-like 3 (METTL3), the core component of N 6-methyladenosine (m6A) writer, is frequently associated with abnormalities in the m6A epitranscriptome in different cancer types, impacting both cancer cells and the surrounding TME. While the impact of METTL3 on cancer cells has been extensively reviewed, its roles in TME and anti-cancer immunity have not been comprehensively summarized. This review aims to systematically summarize the functions of METTL3 in TME, particularly its effects on tumor-infiltrating immune cells. We also elaborate on the underlying m6A-dependent mechanism. Additionally, we discuss ongoing endeavors towards developing METTL3 inhibitors, as well as the potential of targeting METTL3 to bolster the efficacy of immunotherapy.

Dark transformation from 17ß-estradiol to estrone initiated by hydroxyl radical in dissolved organic matter.

The occurrence and fate of 17ß-estradiol (E2) in natural water have gained extensive attention owing to its high ecotoxic risk to wildlife. Dissolved organic matter (DOM) is a ubiquitous water constituent and contributes significantly to E2 removal, although the reaction mechanism is rarely clarified. The present study aims to investigate E2 transformation in water containing fresh or aged DOM surrogates at environmentally relevant concentrations in the dark. Experiments along with radical probes of benzene and furfuryl alcohol reveal that reactive radicals, particularly hydroxyl radical (·OH), formed non-photochemically at higher concentrations in aged DOM than in fresh DOM. The contribution of ·OH in E2 removal is indicated by the decreases in the removal of radical probes in the presence of E2; moreover, E2 removal is inhibited in the presence of radical scavengers. The dose-dependent inhibitive effect of substrate concentrations, including E2 and coexistent propylparaben, shows that the radical concentration is a limiting factor for E2 removal, which could be enhanced by increasing DOM concentration, dissolved oxygen, and light supply. As the main byproduct, estrone (E1) is persistent in the current DOM water in the dark, but it can be easily photodegraded when exposed to light. Theoretical analysis reveals that the initial step is ·OH-initiated H- abstraction on the hydroxyl group in the cyclopentane ring of E2. The formed singlet excited state of E2 undergoes further intramolecular rearrangement and oxidative dehydrogenation to generate E1 and the hydroperoxy radical (·HO2). Considering the universal occurrence of E2 in DOM-rich aquatic matrices, the present findings have special implications for the biogeochemical cycle and risk assessment of this pollutant in natural aquatic environments, particularly those beyond the photic zone.

Contributions of Abiotic and Biotic Processes to the Aerobic Removal of Phenolic Endocrine-Disrupting Chemicals in a Simulated Estuarine Aquatic Environment.

The contributions of abiotic and biotic processes in an estuarine aquatic environment to the removal of four phenolic endocrine-disrupting chemicals (EDCs) were evaluated through simulated batch reactors containing water-only or water-sediment collected from an estuary in South China. More than 90% of the free forms of all four spiked EDCs were removed from these reactors at the end of 28 days under aerobic conditions, with the half-life of 17α-ethynylestradiol (EE2) longer than those of propylparaben (PP), nonylphenol (NP) and 17ß-estradiol (E2). The interaction with dissolved oxygen contributed to NP removal and was enhanced by aeration. The PP and E2 removal was positively influenced by adsorption on suspended particles initially, whereas abiotic transformation by estuarine-dissolved matter contributed to their complete removal. Biotic processes, including degradation by active aquatic microorganisms, had significant effects on the removal of EE2. Sedimentary inorganic and organic matter posed a positive effect only when EE2 biodegradation was inhibited. Estrone (E1), the oxidizing product of E2, was detected, proving that E2 was removed by the naturally occurring oxidizers in the estuarine water matrixes. These results revealed that the estuarine aquatic environment was effective in removing free EDCs, and the contributions of abiotic and biotic processes to their removal were compound specific.