The multifaceted role of 3-methyladenine in cancer therapy.

3-Methyladenine (3-MA), an early autophagy inhibitor, blocks autophagosome formation mainly by inhibiting class III phosphatidylinositol 3-kinase (PI3K) vacuolar protein sorting 34, while its concurrent inhibition of class I PI3K can produce opposing effects on autophagic flux depending on nutrient status. This Review examines the context-dependent roles of 3-MA across cancer types. When autophagy serves a pro-survival function, 3-MA-mediated inhibition tends to attenuate this protective response, thereby potentiating the cytotoxicity of chemotherapeutics, targeted drugs, and natural compounds, and helping to overcome acquired resistance. However, in some settings-such as colorectal cancer without therapeutic pressure-autophagy suppression may instead promote epithelial-mesenchymal transition and metastasis. The pharmacokinetic shortcomings and off-target effects of 3-MA have motivated the design of nanocarriers for tumor-specific co-delivery, aiming to improve bioavailability and avoid paradoxical autophagy induction. Ultimately, the lasting contribution of 3-MA may be its utility as a mechanistic probe that uncovers key autophagy regulatory nodes, paving the way for next-generation selective modulators and biomarker-driven strategies.