FOXO1 in cancer: context-dependent roles, microRNA regulation, and therapeutic opportunities

Forkhead box O1 (FOXO1) is a key transcription factor involved in regulating apoptosis, cell cycle arrest, oxidative stress responses, and metabolic homeostasis. Although FOXO1 traditionally functions as a tumour suppressor, emerging evidence reveals its context-dependent oncogenic role, particularly in cancer stem cells (CSCs) and therapy-resistant cancers. This review explores the complex regulatory network by which microRNAs (miRNAs) modulate FOXO1 expression and activity. Oncogenic miRNAs downregulate FOXO1 or promote its cytoplasmic sequestration via the PI3K/AKT pathway, enhancing tumour proliferation, epithelial-mesenchymal transition, and metastasis. In contrast, tumour-suppressive miRNAs upregulate or activate FOXO1, reinstating cell cycle arrest and apoptosis. Beyond its tumour-suppressive roles, FOXO1 also supports CSC maintenance and therapeutic resistance, highlighting the duality of its function. Notably, FOXO1 overexpression has been shown to improve the metabolic fitness and persistence of chimeric antigen receptor (CAR) T cells in solid tumours, suggesting potential for immunotherapy enhancement. Therapeutic approaches targeting the miRNA-FOXO1 axis, including miRNA mimics, inhibitors, phosphatase modulators, and kinase inhibitors, are promising but require precision to avoid undesirable effects in non-malignant tissues. Comprehensive understanding of FOXO1’s context-specific roles is essential for advancing targeted cancer therapies.