Quercetin inhibits gastric cancer growth and enhances T cells immunity by modulating the PI3K-AKT signaling pathway.

BACKGROUND

Quercetin, a flavonoid derived from astragalus and other medicinal plants, exhibits anti-cancer activity; however, its mechanisms in gastric cancer, especially regarding tumor immunity, remain incompletely understood. The aim of this study is to elucidate the mechanism of quercetin against gastric cancer.

METHODS

Quercetin was evaluated in vitro for the effects on proliferation, apoptosis, cell cycle, mitochondrial potential, and morphology in MKN-45, AGS and normal GES-1 cells. Its efficacy and safety were assessed in vivo using a xenograft model. A "gastric cancer cells + T cells" co-culture system was established to examine quercetin's influence on T cell function. Target prediction employed network pharmacology, molecular docking, and molecular dynamics simulations, with validation via PD-L1 knockdown and PI3K overexpression rescue.

RESULTS

Quercetin significantly inhibited MKN-45 proliferation, induced G0/G1 arrest, and promoted apoptosis, accompanied by mitochondrial damage, loss of membrane potential, downregulation of BCL-2, and upregulation of BAX, CytC, cleaved Caspase-9, and cleaved Caspase-3. In vivo, quercetin reduced tumor growth, decreased Ki-67, increased tumor apoptosis and peripheral CD8+ T cells, with no apparent organ toxicity. In co-culture, quercetin enhanced CD8+ T cell cytotoxicity, increasing granzyme B, perforin, IL-2, and IFN-γ. Mechanistically, quercetin bound PD-L1, reduced its protein expression without affecting mRNA, and suppressed the PI3K-AKT signaling pathway.

CONCLUSION

Quercetin exhibited a dual mechanism: it directly suppressed gastric cancer cell proliferation and induced mitochondria-mediated apoptosis, while also enhancing CD8+ T cell cytotoxicity. Its anti-cancer mechanism involved modulation of PD-L1 protein expression and suppression of the PI3K-AKT signaling pathway. These findings supported the feasibility of quercetin as a potential therapeutic candidate for gastric cancer.