Immunoregulatory role of quercetin in lung cancer

Long-term nourishment with quercetin, a naturally occurring plant flavonoid abundant in citrus fruits, buckwheat, and onions, has been associated with reduced risks of chronic diseases, including cancer. In this study, we evaluated the therapeutic potential and the anti-cancer properties of quercetin in lung cancer using in vitro, in vivo, and ex vivo models. Quercetin induced tumor cell cycle arrest via the p53-p21 axis and suppressed tumor cell migration in both the A549 and H520 human lung cancer cell lines. Moreover, it reduced oxidative stress and downregulated the protein expression of oncogenic markers such as EGFR and PD-L1 on the surface of A549 cells in a dose-response manner. Quercetin significantly attenuated the proliferation and migration of the tumor cells. In an in vivo model, quercetin decreased the tumor load without affecting the body weight. In the ex vivo model, quercetin treatment resulted in the induction of interferon alpha-2 (IFN-α2), a well-known anti-tumor cytokine. These findings demonstrate that quercetin exerts potent anti-tumoral and anti- inflammatory effects in lung cancer by regulating cell cycle, oxidative stress, and immune pathways. Overview of quercetin-induced cellular modulation in lung cancer [Created in BioRender] Quercetin had a direct effect on the tumor cell cycle, where it upregulated CDKN1A and downregulated CDK1 in both murine models and human lung cancer cell lines. Quercetin regulated the p53-p21 axis, decreased EGFR, PD-L1, and Ki67 expression, and also showed a strong inhibitory effect on tumor cell migration. It also conditioned the gut microbiome, promoting an increased abundance of SCFA-producing bacteria. At the same time, it led to an increase in IFN-α2 cytokine production. Quercetin also reprogrammed the splenic CD8 + T cell transcriptome, most notably by upregulating the tumor suppressor gene Ltf while also downregulating several oncogenes involved in proliferation and metastasis, namely POU6F1, Celsr1, ST3GAL6, Sik2, Adnp, and Jun.