The Regulatory Network of FOXM1: Orchestrating Cancer Progression and Resistance to Therapy

Therapy resistance remains a major obstacle to successful cancer treatment and is driven by complex interactions between tumor-intrinsic adaptive mechanisms and signals originating from the tumor microenvironment. Among the molecular regulators implicated in these processes, the transcription factor FOXM1 has emerged as a key mediator of DNA damage repair, cell cycle progression, and stress adaptation. Although FOXM1 has traditionally been studied as a regulator of intracellular signaling pathways, accumulating evidence suggests that its functions extend beyond canonical transcriptional control. In this review, we analyze current knowledge on the mechanisms regulating FOXM1 expression and activity and discuss how FOXM1 contributes to therapy resistance. We propose that FOXM1 should be viewed not merely as a regulator of individual oncogenic pathways but as a systems-level coordinator that integrates intracellular stress adaptation with microenvironment-driven resistance mechanisms. Particular attention is given to the FOXM1 interactome, complemented by an analysis of protein interaction data from BioGRID. We also discuss emerging evidence implicating FOXM1 in intercellular communication. To identify potential links between FOXM1 signaling and extracellular vesicle cargo, we analyzed the overlap between FOXM1 target genes and proteins identified in extracellular vesicle proteome databases. These emerging regulatory networks may represent previously underappreciated contributors to therapy resistance.