Pathology, research and practice · 2026
Licochalcone A targets ADRB2 to enhance CD8+ T cell anti-leukemia activity via regulation involving the AKT2/FOXO1/GLUT2 axis.
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Han Pingping, Wang Huaiyu, Cai Yun, Sun Ye, Zhou Dongzhi
Аннотация
OBJECTIVE: To investigate the effect of Licochalcone A (Lico A) on the function of CD8+ T cells in the tumor microenvironment and its underlying mechanism, and to evaluate its role in enhancing the anti-tumor activity of CD8+ T cells.
METHODS: Flow cytometry was used to analyze the effect of Lico A on the proportion of CD8+ T cells, the expression of activation markers and effector molecules; the in vivo anti-tumor effect of Lico A was evaluated through leukemia tumor-bearing mouse models, CD8+ T cell depletion experiments and adoptive transfer models; meanwhile, glycolysis and related metabolic changes were detected; molecular biology techniques were applied to verify the regulatory relationship of the ADRB2/AKT2/FOXO1/GLUT2 pathway.
RESULTS: Lico A significantly increased the proportion and activation status of CD8+ T cells in the tumor microenvironment, enhanced the expression of effector molecules and reduced early apoptosis. In vivo experiments showed that the tumor volume and weight in the Lico A treatment group were significantly lower than those in the control group, and this effect was dependent on CD8+ T cells. Lico A promoted glycolytic metabolism in CD8+ T cells, up-regulated the expression of GLUT2, and increased the levels of pyruvate, lactic acid and ATP. Molecular docking showed that Lico A stably bound to ADRB2 and inhibited its expression, thereby activating the AKT2/FOXO1 signaling pathway and relieving the transcriptional inhibition of GLUT2 by FOXO1.
CONCLUSION: Lico A appears to act on ADRB2, and the AKT2/FOXO1/GLUT2 axis may be involved in promoting GLUT2-mediated glycolysis, thereby enhancing the survival, activation, and cytotoxic effector function of CD8⁺ T cells in the tumor microenvironment. These findings provide preclinical mechanistic insights into the immunomodulatory activity of Lico A, with the AKT2/FOXO1/GLUT2 pathway emerging as a potentially primary contributing signaling route.
METHODS: Flow cytometry was used to analyze the effect of Lico A on the proportion of CD8+ T cells, the expression of activation markers and effector molecules; the in vivo anti-tumor effect of Lico A was evaluated through leukemia tumor-bearing mouse models, CD8+ T cell depletion experiments and adoptive transfer models; meanwhile, glycolysis and related metabolic changes were detected; molecular biology techniques were applied to verify the regulatory relationship of the ADRB2/AKT2/FOXO1/GLUT2 pathway.
RESULTS: Lico A significantly increased the proportion and activation status of CD8+ T cells in the tumor microenvironment, enhanced the expression of effector molecules and reduced early apoptosis. In vivo experiments showed that the tumor volume and weight in the Lico A treatment group were significantly lower than those in the control group, and this effect was dependent on CD8+ T cells. Lico A promoted glycolytic metabolism in CD8+ T cells, up-regulated the expression of GLUT2, and increased the levels of pyruvate, lactic acid and ATP. Molecular docking showed that Lico A stably bound to ADRB2 and inhibited its expression, thereby activating the AKT2/FOXO1 signaling pathway and relieving the transcriptional inhibition of GLUT2 by FOXO1.
CONCLUSION: Lico A appears to act on ADRB2, and the AKT2/FOXO1/GLUT2 axis may be involved in promoting GLUT2-mediated glycolysis, thereby enhancing the survival, activation, and cytotoxic effector function of CD8⁺ T cells in the tumor microenvironment. These findings provide preclinical mechanistic insights into the immunomodulatory activity of Lico A, with the AKT2/FOXO1/GLUT2 pathway emerging as a potentially primary contributing signaling route.