A review of PI3K/AKT/mTOR inhibitors from traditional Chinese medicine: potential and perspective for activated phosphoinositide 3-kinase δ syndrome.

Activated phosphoinositide 3-kinase δ syndrome (APDS) is a primary immunodeficiency caused by hyperactivation of the PI3K/AKT/mTOR pathway, resulting in severe lymphoproliferation, recurrent infections, autoimmunity, and malignancy. However, current therapies, including immunosuppressants and hematopoietic stem cell transplantation, are constrained by limited efficacy, high costs, donor scarcity, or adverse effects such as metabolic complications from chronic rapamycin use. In this review, we systematically synthesize preclinical evidence on traditional Chinese medicine (TCM) agents that target the PI3K/AKT/mTOR pathway. Our goal is to establish a hypothesis-driven framework for APDS drug discovery. Through a comprehensive PubMed, CNKI, and Wanfang databases up to October 30, 2025, we identified 332 eligible studies, compiling a repository of 5 herbs, 99 extracts, and 56 formulas. These agents, rich in flavonoids, terpenoids, alkaloids, and polysaccharides, exhibit multifaceted pharmacological activities such as antitumor, anti-inflammatory, and immunomodulatory effects. Notably, 15 candidates show promise in ameliorating lymphoproliferation, infection, and gastrointestinal dysfunction in disease models with pathophysiological overlap with APDS. However, we emphasize that all current evidence is derived from non-APDS experimental systems; direct validation in patient-derived immune cells or APDS-mutant models remains absent. This review therefore provides a prioritized, evidence-based repository of testable hypotheses and a translational roadmap, advocating for rigorous functional validation, isoform-specific mechanistic dissection, and integration with conventional therapies to bridge the gap between traditional medicine and precision immunotherapy for APDS.