Renal cell carcinoma (RCC) is a type of solid tumor with one of the highest incidences among urinary system malignancies, and its incidence continues to increase worldwide. The PI3K-AKT-mTOR signaling pathway, as a central signaling hub that regulates biological processes such as cell survival, proliferation, metabolism, and metastasis, often exhibits abnormal and sustained activation during the pathological progression of RCC. Dysregulation of this pathway synergistically promotes tumor progression through multiple mechanisms, including enhancing the survival and clonal expansion of tumor cells, inducing angiogenesis, driving metabolic reprogramming of the tumor microenvironment, and mediating treatment resistance. These pathological changes are closely associated with poor patient prognosis. Given the central role of the PI3K-AKT-mTOR signaling pathway in the pathogenesis of RCC, it has become a key target for targeted therapeutic intervention. Although multiple small-molecule inhibitors targeting this pathway have demonstrated potential for inhibiting tumor growth in preclinical studies and early-phase clinical trials, their clinical application still faces numerous challenges. Against this backdrop, combination therapy strategies offer a new approach to overcome the limitations of single-agent therapy, not only enhancing treatment efficacy but also potentially reducing the risk of drug resistance. Notably, natural products and their derivatives, due to their low toxicity, ability to modulate multiple targets, and specific inhibitory effects on cancer stem cells, are regarded as promising sensitizers in combination therapy. This article systematically reviews the pathological features of RCC and current clinical treatment strategies, with a focus on exploring the molecular regulatory mechanisms of the PI3K-AKT-mTOR signaling pathway in tumor progression, while highlighting the latest research advances in small-molecule inhibitors targeting this pathway. Integrating preclinical mechanistic studies and relevant clinical trial data, the limitations of existing agents are analyzed, and potential optimization directions are proposed, aiming to provide theoretical support and practical references for the clinical translation of precision therapy for RCC and to promote the transformation of pathway-based combination therapy models into clinical applications.
Zou et al. (Fri,) studied this question.