Lung cancer is the second most common cancer with a poor prognosis and no known cure [1]. Non-small cell lung cancer (NSCLC) comprised about 85 % of the newly diagnosed lung cancer cases. Depending on the stage, histology, genetic alterations, and patient’s condition, the treatment approaches in NSCLC usually include surgery, chemotherapy, radiotherapy, immunotherapy, molecularly targeted therapy either alone or in combination. Recent advancements in targeted therapy and immunotherapy have resulted in unprecedented survival benefits in selected patients [2], [3], [4]. However, the overall response and survival rates for NSCLC remain low, particularly in advanced or metastatic disease, and patients who are on targeted therapy or immunotherapy will eventually develop drug resistance [5]. Therefore, continued research into identifying new targets, understanding the resistance mechanisms, and developing novel agents or strategies are required to expand the clinical benefit to a broader patient population and improve NSCLC outcomes.

Artemisinin and its derivatives are the front-line treatment for malaria cases and have saved millions of lives of patients suffering from malaria [6], [7]. Recently, considering its efficacy, tolerance, and clinical safety, considerable research has focused on applying artemisinin derivatives in non-malarial areas, including anti-tumor therapy [8], [9]. Dihydroartemisinin (DHA) is a semisynthetic derivative of artemisinin, and multiple potential mechanisms of action of DHA in NSCLC include anti-proliferative effects [10], anti-angiogenesis [11], and immunomodulating activities [12]. At the same time, a wide range of cellular pathways, including the signal transducer and activator of transcription 3 (STAT3) pathways, have been involved in DHA-mediate anti-cancer effects [13], but until now, the molecular mechanism of DHA in regulating the activity of STAT3 is still elusive.

STAT3 plays a critical role as a central hub for multiple dysregulated signaling pathways in various malignancies, such as lung cancer [14], [15]. Constitutively active STAT3 can upregulate the mRNA levels of many genes involved in tumor cell growth, cell cycle, anti-apoptosis processes, as well as cancer immune escape [16], [17], thus targeting STAT3 is a novel and promising approach in cancer therapy [18], [19]. However, direct targeting of STAT3 at a pharmacologically relevant level remains uncertain, and many studies focus on searching for inhibitors indirectly targeting STAT3 [20], [21]. Interestingly, several recent studies revealed that ROR1-dependent signaling causes autocrine activation of STAT3 [22]. As we know, ROR1 has been shown to play an essential role in embryogenesis, and ROR1 overexpression has been detected in many types of malignant tumors correlated with disease progression [23], [24], [25]. In our previous study, we have already proved the abnormal overexpression of ROR1 on NSCLC cells and the anti-tumor role of DHA in the Lewis Lung cancer mouse model [10], [12], [26], [27], which let us to investigate whether ROR1 could regulate STAT3 signaling pathway in NSCLC, and whether DHA inhibits the activity of STAT3 signaling via targeting ROR1.