Dual Role of IL-6 in Maintaining the resistance of Gastrointestinal stromal tumor and tumor angiogenesis

Resistance is a major obstacle to the effective treatment of many tumor types, including Gastrointestinal stromal tumor (GIST). Although Imatinib (IM) is considered the gold standard for targeted therapy in GIST, resistance to IM ultimately occurs in many patients, leading to disease progression. The precise mechanisms underlying this resistance remain poorly understood. Our study reveals that high expression of Interleukin-6 (IL-6) is closely associated with poor survival outcomes in patients with GIST. Elevated levels of IL-6 not only sustain the viability of GIST cells but also promote tumoral angiogenesis within the tumor microenvironment (TME) via paracrine mechanisms. Notably, the combination of the IL-6 receptor inhibitor Tocilizumab (TCZ) with IM significantly inhibited tumor growth in a GIST xenograft mouse model. Mechanistic investigations indicate that IL-6, through its interaction with IL-6R, reactivates the PI3K/Akt/mTOR signaling pathway, which is suppressed by IM. Additionally, as a secreted protein, IL-6 regulates the secretion of vascular endothelial growth factors controlled by the JAK2/STAT3 signaling pathway in endothelial cells via paracrine action. Thus, IL-6 may serve as a critical biomarker for predicting the prognosis of GIST, and the combined treatment strategy of IM with TCZ shows promising potential in overcoming resistance in GIST.