Apilimod in oncology: From non-malignant origins to emerging anti-cancer potential

Apilimod is an emerging therapeutic compound whose clinical potential has renewed interest in the PIKfyve signaling pathway, a central regulator of endolysosomal trafficking and cellular homeostasis. This review provides a critical overview of the current state of knowledge on Apilimod, spanning early mechanistic studies, preclinical models, and ongoing phase II clinical trials. Apilimod primarily inhibits PIKfyve, leading to profound alterations in vesicular trafficking and vacuolization. Beyond its canonical role in endosomal dynamics, accumulating evidence implicates PIKfyve in broader biological processes, including immune regulation and metabolic control, thereby expanding the potential therapeutic relevance of its pharmacological targeting. Preclinical and clinical studies have suggested possible applications of Apilimod in inflammatory diseases, hematological malignancies, and solid tumors. However, despite encouraging initial findings, important uncertainties remain regarding its precise mechanisms of action, context-dependent efficacy, and safety profile. In particular, the translatability of preclinical observations to clinical benefit, the identification of predictive biomarkers, and the management of potential adverse effects require further investigation. Finally, we discuss emerging therapeutic strategies, including combination approaches with RAS pathway inhibitors, while highlighting the key challenges that must be addressed to fully exploit the therapeutic potential of Apilimod.