Kaempferol's potential in targeting IL-17-mediated inflammatory pathways for colorectal cancer treatment.

Colorectal cancer (CRC) is a leading malignancy with limited treatment options at advanced stages. Interleukin (IL)-17 signaling promotes tumor progression and immune evasion. Kaempferol, a natural flavonol, has anti-inflammatory and antitumor effects, but its role in modulating IL-17 pathways in CRC is unclear. We used an immunocompetent MC38 xenograft model to evaluate kaempferol monotherapy (50/100 mg/kg), its combination with a PD-L1 inhibitor, and IL-17 overexpression. Tumor growth, immune infiltration, cytokines, and signaling pathways were assessed using immunohistochemistry, enzyme-linked immunosorbent assay, flow cytometry, and Western blotting. Kaempferol suppressed tumor growth in a dose-dependent manner and showed synergistic effects with PD-L1 inhibitors. It enhanced CD4+ and CD8+ T cell infiltration, reduced IL-17A+ γδ T cells, and increased IFN-γ+ γδ T cells. Kaempferol also downregulated IL-6, tumor necrosis factor α, and IL-17A and upregulated IL-2 and interferon γ. Molecular analyses showed inhibition of IL-17A, PD-L1, STAT3, and NF-κB pathway activation. IL-17A overexpression reversed these effects, restoring inflammation, immune suppression, and tumor growth. Kaempferol inhibits CRC progression by targeting IL-17-mediated inflammation and improving antitumor immunity, especially when combined with PD-L1 inhibitors. This study supports kaempferol's potential as a novel therapeutic strategy for CRC.