STAT3-driven EMT in cancer metastasis and chemoresistance: A review

Cancer progression and chemotherapy resistance pose significant challenges in treatment, caused by complicated biological mechanisms such as epithelial-mesenchymal transition (EMT). The present review emphasizes the versatile role of STAT3 in facilitating EMT, a process increasing cancer cell mobility, invasiveness, and survival, thereby contributing to the metastasis and chemotherapy resistance. STAT3 demonstrates upregulation in human cancers and regulates key EMT-inducing transcription factors such as TWIST, SNAIL, and ZEB1/2, promoting the transition of epithelial cells to a mesenchymal phenotype. This transformation enables cancer cells to detach from the primary tumor and invade surrounding tissues to reach to distant sites. Furthermore, STAT3 activation within the tumor microenvironment (TME) provides an immunosuppressive niche, supporting tumor growth and resistance to the treatment. The STAT3/EMT axis also enhances chemoresistance by upregulating drug efflux pumps, anti-apoptotic proteins, and survival pathways, enabling cancer cells to cause therapy resistance. Targeting STAT3-mediated EMT through small-molecule inhibitors, RNA interference, or natural compounds shows promise in decreasing chemoresistance and reducing metastasis. However, challenges persist in developing precise inhibitors and unraveling the dynamic nature of EMT. Future research should focus on combination therapies and advanced technologies to highlight the spatiotemporal regulation of STAT3 and EMT, paving the way for the effective strategies to prevent metastasis and improve patient outcomes.