SMAD4-armed oncolytic adenovirus therapy potentiates the chemotherapy effects in NSCLC through suppression of the Wnt/β-catenin pathway.

Non-small cell lung cancer (NSCLC) represents between 80 and 90% of primary lung cancer cases. Despite progress targeting oncogenic drivers, there are no therapies targeting tumor-suppressor loss. This study confirmed a significant downregulation of SMAD4 expression in both NSCLC tissues and cell lines. Loss of SMAD4 was associated with advanced clinical stage, pathological T stage, and poor prognosis for chemotherapy in NSCLC patients. SMAD4 knockdown promoted proliferation, cell cycle progression, migration, and invasion in NSCLC cells, whereas SMAD4 overexpression suppressed these malignant phenotypes. The molecular mechanism underlying SMAD4 loss-driven NSCLC progression links to the abnormal activation of Wnt/β-catenin pathway. Subsequently, an oncolytic adenovirus encoding SMAD4 (OAd CS) was constructed and its efficiency in inhibiting NSCLC growth was assessed. OAd CS selectively replicated in and killed NSCLC cells without affecting the survival of normal lung cells. Mechanistically, CS inhibited NSCLC cell growth through suppressing the Wnt/β-catenin pathway and activating the caspase pathway. Furthermore, combining OAd CS with gemcitabine exhibited superior tumor suppression compared to monotherapy, with no significant toxicity observed in a NSCLC xenograft model. Overall, these findings provide a novel therapeutic target and an additional combination therapy strategy for NSCLC.