STAT3 axis in cancer and cancer stem cells: From oncogenesis to targeted therapies

The signal transducer and activator of transcription 3 (STAT3) is a cytoplasmic transcription factor that is essential in regulating cellular homeostasis. Aberrant and persistent activation of STAT3 triggers the oncogenic progression of multiple cancers. STAT3 can be activated by both canonical and non-canonical pathways, leading to its nuclear translocation and regulation of the transcription of multiple target genes to promote tumor cell proliferation, drug resistance, differentiation, inflammation, immune evasion, and angiogenesis. Persistent activation of STAT3 correlates with the poor prognosis of cancer patients. Notably, STAT3 plays a crucial role in the maintenance of cancer stem cells (CSCs), contributing to disease relapse, metastasis, and poor clinical outcomes. Given its multifaceted role in tumor biology, STAT3 is an attractive target for therapeutic intervention. Various small molecules, peptides, and natural compounds targeting STAT3 are currently under different stages of preclinical and clinical evaluation. Despite promising advances, challenges such as drug resistance, selectivity, and toxicity remain obstacles in the development of effective STAT3-targeted therapies. This review provides a comprehensive overview of STAT3 structure, activation mechanisms, and its functional role in tumor biology and CSC maintenance. We also highlight current progress in STAT3-targeted therapeutic strategies, including agents in clinical trials, and discuss the future potential of STAT3 inhibition in precision oncology.