Abstract
The PI3K/AKT/mTOR signaling axis is a pivotal regulator of key cellular functions, including proliferation, metabolism, survival, and immune modulation. In cancer, its dysregulation drives malignant transformation, tumor progression, therapeutic resistance, and immune evasion. Despite numerous studies, an integrated understanding of this pathway's multifaceted role in tumor biology and treatment remains incomplete. This review comprehensively outlines the oncogenic mechanisms governed by the PI3K/AKT/mTOR pathway, including its regulation of epithelial-mesenchymal transition, autophagy, apoptosis, glycolysis, ferroptosis, and lipid metabolism. We emphasize the dual role of autophagy, its interplay with therapeutic resistance, and its contextual impact on cancer dynamics. Moreover, we explore the epigenetic regulation of this axis by noncoding RNAs (miRNAs, lncRNAs, circRNAs) and its influence on tumor hallmarks. The review also highlights the pathway's involvement in modulating responses to chemotherapy, radiotherapy, and immunotherapy, as well as its role in remodeling the tumor microenvironment. We critically evaluate emerging therapeutic strategies targeting the PI3K/AKT/mTOR axis, including small-molecule inhibitors, phytochemicals, and nanoparticle-based systems. By elucidating the integrated landscape of this pathway, our review highlights its value as a central therapeutic target and offers insights into precision oncology approaches aimed at overcoming drug resistance and enhancing treatment efficacy.