JAK/STAT3 axis in breast cancer: opportunities for intervention with natural phytochemical-based nanotherapeutics

Breast cancer holds a horrifying picture of being one of the most common cancers across the world and with it, comes an even more troublesome morbidity and mortality scenario, especially for high-grade malignancy, such as triple-negative breast cancer. The JAK/STAT3 signaling pathway is one of the well-established oncogenic drivers for breast cancer in regard to tumor cell proliferation, survival, metastasis, immune evasion, and resistance to therapy. Natural phytochemicals, including resveratrol, show promising STAT3 inhibitory activity but have a limited clinical application due to their poor solubility, low bioavailability, and metabolic instability. Nanotechnology may be the best system to solve these problems by improving the pharmacokinetic properties and tumor-targeting abilities of phytochemicals. This review describes the pathophysiological role of STAT3 in breast cancer and discusses the chances of therapeutic exploitation via natural compounds, especially resveratrol, delivered via advanced nanoformulations; polymeric, lipid-based, and magnetic nanoparticles. A special approach was taken with respect to magnetic nanoparticles loaded with resveratrol, which offer a dual benefit of targeted therapy with imaging capabilities. Although preclinical results have been encouraging, transferring to successful clinical development will involve hurdles inherent to formulation complexity, regulatory compliance, safety, and patient-specific optimization approaches. Quality-by-design principles along with biomarker-driven strategies may lead to better advances in phytochemical-loaded nanoparticles becoming clinically promising STAT3-targeted breast cancer treatments.