Orchestration of the tumor microenvironment by citrus flavonoids: from preclinical mechanisms to translational therapeutic

Malignant lung tumors are the leading cause of cancer-related mortality worldwide, and therefore remodeling of the tumor microenvironment (TME) has become an important strategy to overcome anti-tumor therapy resistance in lung cancer. Flavonoid components isolated from Citri Reticulatae Pericarpium (CRP), such as nobiletin, hesperidin, and tangeretin, have been shown to modulate the lung cancer TME in a highly relevant manner. The present narrative review collected literature from the PubMed, Web of Science, Embase, CNKI, and Wanfang databases between 2016 and 2026, and hence discussed the molecular mechanisms by which CRP flavonoids reshape the lung cancer TME, namely their regulation of oxidative stress-inflammation homeostasis, correction of lipid metabolic reprogramming, induction of pyroptosis, and inhibition of epithelial-mesenchymal transition. Discussion of the role of EMT and tumor angiogenesis suppression were also presented. Then evidence regarding the modulation of emerging targets was introduced, namely ferroptosis and the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, which are both promising targets in lung cancer models. Translational prospects of CRP flavonoids were led to enhancing immune checkpoint inhibitor (ICI) efficacy and developing nano-delivery systems. The article first outlined the fundamental barriers, then gave a very systematic and critical review of the contradictory findings, context-dependent effects, and methodological limitations in the existing literature; and then pointed out the gaps in frontier research. Therefore, it provides an excellent theoretical foundation for the research and development of anti-lung cancer drugs from CRP flavonoids, while also objectively identifying the current knowledge gaps and clinical translation bottlenecks.