To the editor,
We followed with interest the report by Zeng et al. on the blocking METTL1–TGF‐β2–PMN‐MDSC axis is a therapeutic strategy to restore antitumor immunity and prevent hepatocellular carcinoma (HCC) recurrence after radiofrequency ablation (RFA) treatment.1 Considering the diversity of HCC‐associated signaling pathways and the existence of immune‐suppressive tumor microenvironment (TME), the treatment of HCC was complicated. The recurrence of HCC after RFA was one of the major problems in the treatment of HCC. We appreciated that their findings shed light on the research of antirecurrence for patients with HCC after RFA. However, after reading this article, we would like to highlight some important issues in this study.
First, we found that the article lacked descriptions of the degree of liver fibrosis and the level of viral replication in patients with HCC. According to previous research results, the signaling pathways activated by different degrees of fibrosis and viral replication levels were not the same.2 Therefore, we thought the authors should have stated this in the manuscript. The authors could further quantitatively compare the degree of liver fibrosis in different patients through techniques such as FibroScan. These efforts will contribute to the credibility of their findings.
Second, we observed that critical information such as the patients’ Barcelona Clinic Liver Cancer stage, tumor number, and tumor size were ignored. The authors only reported the age and sex of the enrolled patients and lacked information on whether the patients had received antiviral therapy, transarterial chemoembolization, targeted therapy, or immunotherapy before RFA. All of these factors were key regulators of the TME, and the lack of this information might threaten the reproducibility of this study.
Third, the authors used mouse models to investigate the effects of complete RFA and insufficient RFA (iRFA) on tumor growth patterns and the microenvironment. iRFA created an ischemic environment inside the tumor. Studies had shown that METTL1 could also mediate angiogenesis after ischemia by promoting the translation of Vascular Endothelial Growth Factor A messenger RNA.3 We had reason to believe that METTL1 might promote HCC recurrence through multiple mechanisms. Therefore, targeting a single pathway might not achieve the desired therapeutic effect.
In conclusion, the authors discovered the METTL1–TGF‐β2–PMN‐MDSC axis underlying the high recurrence rate of HCC after RFA. This pathway could be used to guide the development of antirelapse drugs. However, given the multiple biological functions of METTL1, combinations of drugs targeting multiple pathways may be required.
Supported by: the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (CIFMS (No. 2020-I2M- C& T-B- 026), the CIFMS (No. 2020-I2M- C& T-B- 019), Chen Xiao-Ping Foundation for the Development of Science and Technology of Hubei province (CXPJJH1200008-10), and Beijing Municipal Natural Science Foundation Project (Grant No. 7222130).
CONFLICT OF INTEREST
Nothing to report.
1. Zeng X, Liao G, Li S, Liu H, Zhao X, Li S, et al. Eliminating METTL1‐mediated accumulation of PMN‐MDSCs prevents HCC recurrence after radiofrequency ablation. Hepatology. 2022. https://doi.org/10.1002/hep.32585
2. Bender D, Hildt E. Effect of hepatitis viruses on the Nrf2/Keap1‐signaling pathway and its impact on viral replication and pathogenesis. Int J Mol Sci. 2019;20:4659.
3. Zhao Y, Kong L, Pei Z, Li F, Li C, Sun X, et al. m7G methyltransferase METTL1 promotes post‐ischemic angiogenesis via promoting VEGFA mRNA translation. Front Cell Dev Biol. 2021;9:642080.