Overcoming mTOR Inhibitor Resistance: From Biological Basis to Therapeutic Strategies

Resistance to mTOR inhibition is mediated by multiple adaptive mechanisms, including feedback activation of the PI3K/AKT/mTOR pathway, autophagic adaptation, metabolic reprogramming, immune evasion, tumor heterogeneity, and microenvironmental crosstalk. Recent research has also elucidated the crucial role of RNA modifications, particularly m6A methylation, and the regulatory impact of non-coding RNAs in facilitating tumor adaptation to mTOR blockade. Accordingly, novel therapeutic approaches are emerging. The combination of PI3K/AKT/mTOR inhibitors with immune checkpoint blockades represents a promising strategy for overcoming therapeutic resistance. Additionally, next-generation mTOR inhibitors and synthetic lethality strategies are being tailored to target specific tumor profiles. Furthermore, advancements in multi-omics technologies and AI-powered predictive models are transforming personalized cancer treatment. This comprehensive review delves into the molecular intricacies of mTOR inhibitor resistance and explores innovative strategies aimed at enhancing therapeutic outcomes and improving patient responses.