Abstract Background Lung adenocarcinoma (LUAD), as the main subtype of non-small cell lung cancer, still faces challenges such as drug resistance and systemic toxicity in treatment. Cuproptosis is an emerging form of cell death that is less likely to develop resistance and has high tumor selectivity. As a metabolically active tumor cell, LUAD has copper accumulation in its intracellular environment, making it an ideal target for cuproptosis-targeted therapy. However, existing cuproptosis inducers have problems such as strong off-target toxicity, poor water solubility, and the weakening of therapeutic efficacy by the antioxidant system in the tumor microenvironment (TME). Therefore, there is an urgent need to find materials with good water solubility and the ability to target deliver cuproptosis to LUAD for precise treatment. Methods We conducted computer simulation screening of the protein products of core prognostic genes through bioinformatics methods to identify potential targeted drugs. We innovatively adopted a metal-polyphenol coordination self-assembly strategy to construct a water-soluble and more stable nano-drug, Fe-Que, through the synergistic coordination of iron ions and the drug (Que). Results This nanostructure can respond to the acidic pH and high concentration of glutathione (GSH) in the TME to in situ dissociate and release active Que and Fe³+. The released Fe³+ not only consumes GSH to weaken the antioxidant defense ability of tumor cells but also catalyzes the endogenous H2O2 to generate highly toxic ·OH through valence state transformation, thereby achieving a “two birds with one stone” dual-pathway amplification of ferroptosis. The tumor-associated antigens and damage-associated molecular patterns released during this process effectively promote the maturation of dendritic cells and the infiltration of cytotoxic T lymphocytes, converting “cold tumors” into an immune-inflammatory environment and sensitizing LUAD to immunotherapy. Conclusion This study successfully developed a novel nebulized nano-drug, which amplifies ferroptosis through dual pathways in a synergistic manner and simultaneously initiates an in situ “vaccine” effect. This lays a theoretical foundation for reversing the immunosuppressive microenvironment and combining immunotherapy, providing a promising new strategy for the treatment of LUAD. This abstract is funded by: the National Natural Science Foundation of China (32172894), Academic Leaders Training Program of Pudong Health Committee of Shanghai (Grant No. PWRd2022-09), and the Scientific Research Project of Shanghai Pudong Hospital (YJYJRC202106)
Lili et al. (Fri,) studied this question.