From metabolic remodeling to therapeutic intervention: research progress on SLC7A5 in cancer

Solute Carrier Family 7 Member 5 (SLC7A5) is a key member of the solute carrier transporter family that mediates the transmembrane transport of large neutral amino acids (LNAAs). Its expression is precisely regulated by a multilayered network encompassing transcription factors, non-coding RNAs, and RNA/protein epigenetic modifications. In various malignant tumors, SLC7A5 drives amino acid metabolic reprogramming by taking up essential amino acids (EAAs) such as leucine to activate the Mammalian Target of Rapamycin Complex 1 (mTORC1) signaling pathway. Concurrently, SLC7A5 is deeply involved in tumor immune microenvironment (TIME), ferroptosis, redox homeostasis, epigenetic modification, and integrated stress response (ISR), and is closely associated with tumor proliferation, invasion, metastasis, and poor prognosis. In solid tumors such as colorectal cancer (CRC) and breast cancer, SLC7A5 exhibits dual value as both a prognostic biomarker and a therapeutic target. Highly selective inhibitors represented by JPH203 have completed early-phase clinical trials in biliary tract cancer. However, adaptive drug resistance, systemic immunotoxicity, and individualized patient selection remain key challenges facing its clinical translation. This review systematically summarizes the regulatory mechanisms of SLC7A5, its molecular functions in driving tumor progression, the clinical significance in different solid tumors, and recent advances in targeted inhibitors development and therapeutic strategy optimization, aiming to provide a theoretical basis and clinical reference for precision metabolic intervention targeting SLC7A5.