YTHDF1-targeting nanoassembly reverses tumoral immune evasion through epigenetics and cell cycle modulation

Abstract

YTHDF1, as a key m⁶A reader protein, is believed to be one of the key mechanisms leading to tumor cell immune evasion and resistance via promoting MHC-I degradation. We explore therapeutic strategies that combine iron metabolism regulation with epigenetic regulation. Here, a nanoassembly that integrates Deferasirox (DFX, an FDA-approved iron chelator) and YTHDF1 siRNA (known as PPD/siYTHDF1) has been developed, which jointly promotes cell cycle arrest in tumor cells by interfering with iron metabolism and knocking down YTHDF1 protein. At the same time, YTHDF1 deficiency inhibits the mRNA translation of lysosome-related proteins, upregulates MHC-I molecule expression (2.5-fold), reduces the degradation of internalized antigens, enhances T cell-mediated immune response, and ultimately restores tumor immune surveillance and triggers powerful anti-tumor immune efficacy. After treatment, CD8⁺ T cells in the tumor site increased by 2.2-fold, and effector memory T cells in the spleen increased by 2.1-fold. It demonstrates a highly effective anti-tumor effect in breast cancer treatment, as well as in postoperative anti-recurrence and anti-metastasis models.