Systems-level Reprogramming of PI3K/AKT/mTOR Signaling by Curcumin and Resveratrol: Feedback Plasticity, Metabolic Integration, and Therapeutic Network Destabilization in Cancer

The PI3K/AKT/mTOR (PAM) signaling axis is a central regulator of tumor growth, metabolic reprogramming, survival, and therapeutic resistance across multiple cancer types. Although pharmacological inhibitors targeting individual PAM components have demonstrated clinical utility, their long-term efficacy is frequently limited by signaling redundancy, compensatory feedback activation, metabolic adaptation, and tumor microenvironment-driven plasticity. Consequently, increasing attention has focused on multi-targeted strategies capable of modulating adaptive oncogenic networks rather than isolated signaling nodes. Curcumin and resveratrol are pleiotropic phytochemicals with broad regulatory effects on PAM-associated signaling. This review examines whether these compounds function merely as canonical pathway inhibitors or as systems-level modulators capable of destabilizing adaptive oncogenic signaling networks. We critically synthesize mechanistic and translational evidence describing the effects of these phytochemicals on receptor tyrosine kinases, PI3K/AKT/mTOR signaling, mTORC2-mediated feedback loops, metabolic regulation, inflammatory signaling, hypoxia-associated pathways, apoptosis, and tumor microenvironment interactions. Emerging evidence suggests that curcumin and resveratrol may attenuate adaptive resistance by simultaneously modulating metabolic, inflammatory, stromal, and immune-associated signaling processes that reinforce PAM pathway activity. This review further evaluates translational challenges that continue to limit clinical application, including poor bioavailability, rapid metabolism, pharmacokinetic instability, variable tissue exposure, and formulation heterogeneity. Recent advances in nanoformulation, blood–brain barrier-targeted delivery, and combinatorial therapeutic strategies are discussed as potential approaches to improve pharmacological performance and therapeutic integration. We also highlight unresolved systems-level questions involving signaling plasticity, biomarker-guided patient stratification, adaptive therapy, and network-level pharmacodynamic assessment. Overall, this review proposes a systems-pharmacology framework in which curcumin and resveratrol are interpreted not as isolated pathway blockers, but as multi-context modulators capable of influencing adaptive oncogenic network behavior. Such a perspective may support the future development of biomarker-guided combinatorial strategies within precision oncology paradigms.