The Role of Hedgehog Signaling in Non-small Cell Lung Cancer: Targeting Tumor Invasion, Therapy Resistance and Novel Therapeutic Strategies

Although essential for normal development and tissue homeostasis, aberrant activation of the Hedgehog (Hh) signaling pathway is implicated in non-small cell lung cancer (NSCLC) progression and treatment resistance. This review details the contribution of Hh signaling to NSCLC, focusing on its promotion of tumor invasion and therapeutic resistance, and establishes a rationale for disrupting this pathway to improve treatment efficacy. Malignant phenotypes in NSCLC are driven by dysregulated Hh pathway activity, often via autocrine or paracrine loops. We specifically assess how Hh pathway activation enables tumor invasion, metastasis, and the development of drug resistance. The review elucidates key resistance mechanisms against diverse therapies-encompassing chemotherapy, targeted therapy and immunotherapy-with a focus on epithelial-mesenchymal transition (EMT), cancer stem cell maintenance, and multidrug resistance (MDR). Therefore, combining Hh pathway inhibitors with standard therapies represents a promising approach for managing treatment-resistant NSCLC.