Licoisoflavone A potentiates oxaliplatin efficacy in colorectal cancer by dual targeting arginine metabolism of tumor microenvironment and cancer cells.

BACKGROUND

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality, with resistance to oxaliplatin (Oxa) and its associated side effects posing major therapeutic challenges. Natural flavonoids have shown potential in the prevention and treatment of CRC.

PURPOSE: This study aimed to investigate whether combining Oxa with the bioactive flavonoid licoisoflavone A (LA) derived from Glycyrrhiza species could exert enhanced antitumor effects against CRC and to explore the underlying mechanisms.

METHODS

A CT26 tumor-bearing mouse model was established to evaluate the therapeutic efficacy of Oxa in combination with LA in vivo. Mass spectrometry-based proteomics and metabolomics analyses were performed to identify differentially expressed proteins and metabolites between the Oxa group and the Oxa plus LA group. Differential expressed proteins and associated pathways were subsequently validated in HCT116 cells, SW480 cells, and patient-derived organoids. Furthermore, two complex organoid models-an organoid-lymphocyte co-culture system and an air-liquid interface organoid system-were developed to investigate the underlying mechanisms. Flow cytometry and Western blot analyses were employed in both in vitro and in vivo settings.

RESULTS

The combination of LA and Oxa significantly inhibited tumor growth in CT26 tumor-bearing mice. Arginine metabolism was significantly reduced following LA treatment. Arginase-1 (ARG1) was identified as a potential target of LA. LA significantly downregulated ARG1 expression, which was associated with an increased proportion of CD8⁺ T cells and reduced expression of CD69⁺ and PD-1, suggesting a potential alleviation of T cell exhaustion-related features. Moreover, LA inhibited CRC cell proliferation by suppressing ARG1-mediated activation of the PI3K/Akt/mTOR signaling pathway.

CONCLUSIONS

LA is a natural flavonoid that targets arginine metabolism and enhances the therapeutic efficacy of Oxa in CRC treatment.