Natural compounds for non-small cell lung cancer treatment: focus on the EGFR signaling pathway

The EGFR signaling pathway is a critical driver in the occurrence and development of non-small cell lung cancer (NSCLC). However, the inevitable development of acquired resistance to EGFR tyrosine kinase inhibitor (TKI) poses a major therapeutic challenge. Natural compounds, with their intrinsic multi-target capabilities and favorable safety profiles, represent a promising strategy for overcoming this resistance. This review provides a critical synthesis of current evidence for over 33 representative natural compounds—spanning alkaloids, terpenoids, flavonoids, and polyphenols—with a focus on their mechanisms for enhancing TKI efficacy. These include direct inhibition of EGFR activation, regulation of key downstream signaling pathways, and induction of programmed cell death. Furthermore, it also examine how emerging approaches such as nano-delivery systems can overcome the pharmacokinetic limitations of these compounds. Ultimately, this review provides a novel, strategy-oriented perspective by framing natural compounds not merely as standalone agents, but as essential components of rational combination therapies, thereby offering a fresh roadmap for their clinical translation in precision oncology for NSCLC.