MC1R regulates T regulatory cells differentiation through metabolic reprogramming to promote colon cancer

Abstract

Background By 2021, colon cancer was a leading global cancer, with early detection improving outcomes but advanced cases still having poor prognosis. Therefore, understanding its molecular mechanisms is crucial for developing new preventive and therapeutic strategies. Methods In our study, we leveraged the TCGA database to assess MC1R expression in colon cancer and its link with patient prognosis. Further, employing mouse models and diverse experimental techniques, we investigated MC1R's impact on colon cancer progression and elucidated its underlying mechanism. Results In a follow-up study of clinical patients, MC1R was identified as having an important role in the development of colon cancer. First, it was found that MC1R was more highly expressed in colon tumor tissues than in adjacent tissues. In addition, we found that MC1R was associated with the prognosis of colon cancer, and higher expression of MC1R tended to predict a worse prognosis. To verify the reliability of this conclusion, we obtained MC1R^−/− mice, which showed a greater ability to resist tumor growth than wild-type mice, as expected. To further explore the mechanism, we conducted a series of experiments. Further investigation revealed that the portion of Tregs in MC1R^−/− mice changed significantly, while the portion of CD4 + and CD8 + T cells remained unchanged. The in vitro experiments also found that the MC1R^−/− T cells had a weaker ability to differentiate into Tregs. Previous studies have found that the functional integrity of Tregs is interwoven with cellular metabolism. Therefore, we deduced that MC1R regulated the differentiation of Tregs by reprogramming metabolism. As expected, MC1R^−/− T cells showed weaker mitochondrial function and a lower aerobic oxidation capacity. At the same time, the MC1R^−/− T cells obtained stronger limiting effects on colon cancer cells. According to these experimental results, the inhibitor of MC1R came to our sight as a potential therapeutic agent to suppress colon cancer. The results showed that when we suppressed MC1R, the tumors in the mice developed more slowly, and the mice survived longer, which may provide a novel strategy for treating clinical colon cancer in the future. Conclusion By regulating the differentiation of Tregs, MC1R overexpression in colon cancer correlates with poor prognosis, and MC1R inhibition shows potential as a therapeutic strategy to slow tumor growth and enhance survival.