Natural Products Targeting the PI3K/Akt/mTOR-Mediated Autophagy Pathway in Cancer Therapy: Recent Advances and Clinical Perspectives

Dysregulation of the phosphoinositide 3-kinase/protein kinase B/mammalian target of the rapamycin (PI3K/Akt/mTOR) pathway and its complex interplay with autophagy is a crucial mechanism driving proliferation, survival, and therapeutic resistance in cancer. Natural products offer a vast chemical library for exploiting this axis of chemistry to treat diseases. This review synthesizes and evaluates recent advances (2015-2025) in natural products that target PI3K/Akt/mTOR-mediated autophagy. We elucidate the mechanisms by which diverse natural product classes, such as alkaloids, flavonoids, terpenoids, and polyphenols, modulate this pathway, effectively affecting autophagic flux to suppress proliferation and enhance apoptosis across various tumor models. We analyze the burgeoning evidence for natural products in combination with chemotherapy, targeted agents, and immunotherapy, highlighting their ability to enhance efficacy, reduce toxicity, and reverse drug resistance. Despite promising preclinical data, significant translational hurdles, primarily poor pharmacokinetic properties, persist. By integrating mechanistic insights, synergistic strategies, emerging clinical data, and translational challenges, this review provides a comprehensive framework for advancing PI3K/Akt/mTOR-autophagy-modulating natural products from in vitro cytotoxic leads and in vivo antitumor candidates toward clinical translation..