Apigenin 7-glucoside reprograms tumor metabolism and enhances immunotherapy efficacy in colorectal cancer via DLX5

Background: The progression of colorectal Cancer (CRC) is closely associated with glycolysis, angiogenesis and immune response. While the natural flavonoid Apigenin 7-glucoside (A7G) exhibits anti-tumor potential, its effects on these three processes remain unclear. This study aims to investigate the impact of A7G on the CRC landscape and to assess its synergistic effect when combined with PD-1 inhibitors.

Methods: Western blotting was used to detect the effect of A7G on glycolysis and angiogenesis-related factors. Immunohistochemistry and flow cytometry were employed to analyze changes in the tumor immune microenvironment. The CT26 mouse xenograft model with overexpressed DLX5 was established to evaluate the role of A7G in modulating metabolic and immune responses. Finally, the therapeutic effect of A7G in combination with PD-1 inhibitors was explored.

Results: A7G significantly decreased the expression of glycolysis and angiogenesis-related factors, a process partially reversed by DLX5 overexpression. Flow cytometry analysis showed that A7G treatment increased the ratio of CD4⁺ T cells/CD8⁺ T cells and reduced the infiltration of M2 macrophages and Treg cells, which was also modulated by DLX5. When combined with PD-1 inhibitors, A7G markedly suppressed tumor growth and enhanced the efficacy of immune therapy.

Conclusion: A7G treatment demonstrated potential anti-tumor activity in CRC, which is characterized by the simultaneous attenuation of glycolysis and immune evasion via the DLX5 axis. When used in combination with PD-1 inhibitors, A7G significantly enhances the effects of immunotherapy, providing a novel strategy for Cancer treatment.

Colorectal cancer; Glycolysis; Tumor immune microenvironment.