Targeting mTOR Signaling in Cancer: The Promise of Natural Product-derived Inhibitors

Recent advances in cancer biology have revolutionized the development of targeted and combination therapies, offering new avenues for improving cancer management. Among the central molecular regulators, the mammalian target of rapamycin (mTOR) plays a pivotal role in orchestrating cell growth, metabolism, and survival. Aberrant activation of mTOR signaling driven by genetic mutations or dysregulation of upstream pathways such as phosphoinositide 3-kinase (PI3K)/AKT has been strongly implicated in cancer progression, metastasis, and therapeutic resistance. Consequently, mTOR has emerged as a promising target for anticancer drug development. Although synthetic mTOR inhibitors, including rapamycin and its analogs (rapalogs), have shown clinical benefits, their limited efficacy and the emergence of resistance have highlighted the need for novel strategies. Natural product-derived mTOR modulators have gained increasing attention due to their multi-targeted mechanisms of action, simultaneously modulating mTOR and its upstream or parallel signaling networks. These compounds exhibit potent anticancer properties, including suppression of tumor growth, induction of apoptosis, and reversal of drug resistance. This review elucidates the biological functions of mTOR in tumorigenesis and delineates its regulatory mechanisms underlying malignant phenotypes. Furthermore, it emphasizes the therapeutic promise of natural products as a rich source of mTOR inhibitors, providing insights for the rational design of innovative cancer therapies and combination regimens.