Multitarget Antitumor Effects of Natural Products and Approved Drug Repurposing in Lung Cancer: Advances in Mechanisms, Combination Regimens, Delivery System Optimization, and Clinical Challenges

Lung cancer is one of the leading causes of cancer-related mortality. The effectiveness of treatment is limited by several factors, including significant tumoral heterogeneity, rapid development of drug resistance, high metastatic potential, and a complex tumor microenvironment. In recent years, natural products have emerged as valuable resources for the discovery of novel anti-tumor strategies against lung cancer. These compounds possess diverse chemical properties, target multiple pathways, are abundant in nature, and exhibit relatively low toxicity. The utilization of existing medications with established pharmacokinetic profiles and safety records, combined with shorter development timelines, shows promise for advancing lung cancer treatment research. A growing body of evidence indicates that both naturally occurring compounds and commercially available drugs exert effects that extend beyond traditional cytotoxic mechanisms. These agents influence processes such as ferroptosis, oxidative stress, metabolic reprogramming, autophagy, apoptosis, epithelial-mesenchymal transition (EMT), tumor immune microenvironments, and epigenetic networks, suggesting that their activities can be leveraged for a robust multi-target anti-tumor strategy. Accordingly, this review systematically reviews the research advancements regarding natural products and the repurposing of marketed drugs in lung cancer, summarizes their potential for combination with chemotherapy, targeted therapy, radiotherapy, and immunotherapy, and discusses future directions for clinical translation.