Vitexin antagonizes the kynurenine pathway via AhR inhibition to reprogram tumor-associated macrophages and enhance antitumor immunity in lung adenocarcinoma.

This study aims to elucidate the potential regulatory mechanism of Vitexin in lung adenocarcinoma (LUAD) and its role in tumor-associated macrophages (TAMs) modulation. First, candidate targets of Vitexin for the treatment of LUAD were screened through bioinformatics analysis. Subsequently, an M2 polarization model of TAMs was constructed in vitro, and relevant indicators were detected by quantitative real-time polymerase chain reaction (qRT-PCR), Western blot, immunofluorescence, Transwell, and enzyme-linked immunosorbent assay (ELISA) experiments. Meanwhile, a nude mouse subcutaneous lung cancer transplantation model was used in vivo to verify the regulatory effect of Vitexin on the immune microenvironment. The study found that aryl hydrocarbon receptor (AhR) is a potential target of Vitexin, and its high expression in LUAD is associated with poor prognosis; Vitexin can inhibit the nuclear translocation of AhR, antagonize the Kyn-induced M2 polarization of macrophages, promote a shift in macrophage metabolic markers, and simultaneously inhibit tumor cell migration and induce apoptosis. In vivo experimental results further confirmed that Vitexin can block the Kyn-AhR pathway, effectively inhibit tumor growth, regulate the secretion of interleukin-10 (IL-10) and tumor necrosis factor-α (TNF-α), and promote the conversion of TAMs to the M1 phenotype. In summary, vitexin may regulate the IDO1-Kyn-AhR signaling axis and modulate macrophage polarization and metabolic state in LUAD, suggesting its potential role as an adjunctive therapeutic candidate in LUAD.