A Methionine Allocation Nanoregulator for the Suppression of Cancer Stem Cells and Support to the Immune Cells by Epigenetic Regulation

Abstract Epigenetic dysregulation is prevalent in human cancers, affecting gene expression and metabolic patterns to meet the demands of malignant evolution and abnormal epigenetic processes, and resulting in a protumor immune microenvironment. Tumors require a steady supply of methionine for maintaining epigenetic flexibility, which is the only exogenous precursor of methyl donor S‐adenosylmethionine for methylation, crucial for their resistance to therapies and survival in a nutrient‐deficient microenvironment. Thus, tumor cells upregulate the Lat4 transporter to compete and deprive methionine in the microenvironment, sustaining their malignant phenotypes and also impairing immune cell functions. Addressing this methionine addiction is the key to overcoming drug resistance and improving immune response. Despite the challenge of lacking specific Lat4 inhibitors, an oxaliplatin prodrug crosslinked fluorinated polycation/anti‐Lat4 small interfering RNA complex nanoregulator (AS‐F‐NP) has been designed and developed here. This nanoregulator restricted the greedy methionine uptake of tumor cells by knocking down Lat4, which in turn inhibited the malignant evolution of the tumor while restoring the viability and function of tumor‐infiltrating immune cells.