STAT3 and neoplasm: Among the most well-characterized pathways, IL-6 secreted by CAFs and tumor-associated macrophages activates STAT3 signaling in CSCs, increasing the expression of stemness-associated transcription factors such as SOX2, OCT4, and NANOG.245,246 Persistent IL-6/STAT3 activation enhances therapeutic resistance and EMT, promoting metastasis.