Insights into IL-6/JAK/STAT3 signaling in the tumor microenvironment: Implications for cancer therapy

The IL-6/JAK/STAT3 signaling pathway is a key regulator of tumor progression, immune evasion, and therapy resistance in various cancers. Frequently dysregulated in malignancies, this pathway drives cancer cell growth, survival, angiogenesis, and metastasis by altering the tumor microenvironment (TME). IL-6 activates JAK kinases and STAT3 through its receptor complex, leading to the transcription of oncogenic genes and fostering an immunosuppressive TME. This environment recruits tumor-associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), and regulatory T cells (Tregs), collectively supporting immune evasion and tumor growth. IL-6/JAK/STAT3 axis also contributes to metabolic reprogramming, such as enhanced glycolysis and glutathione metabolism, helping cancer cells adapt to environmental stresses. Therapeutic targeting of this pathway has gained significant interest. Strategies include monoclonal antibodies against IL-6 or its receptor (e.g., Tocilizumab, Siltuximab), JAK inhibitors (e.g., Ruxolitinib), and STAT3-specific inhibitors (e.g., Napabucasin), which have exhibited promise in preclinical and initial clinical studies. These inhibitors can suppress tumor growth, reverse immune suppression, and enhance the efficacy of immunotherapies like immune checkpoint inhibitors. Combination therapies that integrate IL-6 pathway inhibitors with conventional treatments are particularly promising, addressing resistance mechanisms and improving patient outcomes. Advances in biomarker-driven patient selection, RNA-based therapies, and isoform-specific inhibitors pave the way for more precise interventions. This review delves into the diverse roles of IL-6/JAK/STAT3 signaling in cancer progression, therapeutic strategies targeting this pathway, and the potential for integrating these approaches into personalized medicine to enhance treatment outcomes.