We sincerely appreciate Professor Naoshi Nishida for his valuable and insightful comments regarding our recently published article titled “Integrated Molecular Characterization of Sarcomatoid Hepatocellular Carcinoma” [1]. His comments not only summarized the gene mutations, expression, and tumor immune microenvironment (TIME) of sarcomatoid hepatocellular carcinoma (HCC), but also pointed out the direction of future study [2].

Sarcomatoid HCC is a rare histological subtype of HCC with a highly aggressive nature, which is characterized by combined features of epithelial (HCC) and mesenchymal (sarcoma) [3-5]. Patients with sarcomatoid HCCs are frequently diagnosed at an advanced stage with a larger tumor size or lymph node metastasis [6]. These characteristics contribute to an extremely poor prognosis and a high risk of recurrence and metastasis [4]. In our study, we found that ARID2 mutation was enriched in patients with sarcomatoid HCC, which suggests a potentially crucial role of ARID2 mutation in sarcomatoid HCC pathogenesis. Moreover, we revealed different transcriptional characteristics in sarcomatoid HCCs. We found that several signaling pathways, including cell adhesion, cell migration, especially the epithelial–mesenchymal transition (EMT) pathway, were upregulated in sarcomatoid tumor components.

In our study, we found that genomic alteration (ARID2 mutation) together with the tumor microenvironment (hypoxic microenvironment) leads to EMT of HCC cells, which may contribute to the formation of the sarcomatoid tumor component, leading to sarcomatoid HCC development and progression [1]. These results indicated that overcoming the tumor hypoxic microenvironment and targeting EMT progress might be effective therapeutic strategies for sarcomatoid HCC patients [7-10].

However, there are several shortcomings in our research. Other than ARID2 mutation, we did not detect any mutations that occurred more frequently in patients with sarcomatoid HCC than in those with non-sarcomatoid HCC. Moreover, we could not detect specific mutations in the sarcomatoid tumor components compared with the conventional HCC components. We speculated that this might be related to the limited sample size. We plan to recruit a larger group of patients with sarcomatoid HCC in further studies to explore whether other mutations besides ARID2 occur more frequently in patients with sarcomatoid HCC than in those with non-sarcomatoid HCC, and determine if there are mutations specifically detected in the sarcomatoid components.

As Professor Naoshi Nishida noted, molecular targeted agents (MTAs) and immune checkpoint inhibitors (ICIs) have been introduced for the treatment of HCC [11]. However, sarcomatoid HCC is often excluded from clinical trials of pharmacological therapies for HCC, and standard drugs specifically effective against sarcomatoid HCC have not been developed. In light of this condition, understanding the genetic and transcriptional profiles of sarcomatoid HCC, as well as the features of its TIME, is essential for the development of MTA- and ICI-based therapeutic strategies [12].