Advance of SOX Transcription Factors in Hepatocellular Carcinoma: From Role, Tumor Immune Relevance to Targeted Therapy

SIMPLE SUMMARY: Hepatocellular carcinoma (HCC) is one of the deadliest human health burdens worldwide. However, the molecular mechanism of HCC development is still not fully understood. Sex determining region Y-related high-mobility group box (SOX) transcription factors not only play pivotal roles in cell fate decisions during development but also participate in the initiation and progression of cancer. Given the significance of SOX factors in cancer and their ‘undruggable’ properties, we summarize the role and molecular mechanism of SOX family members in HCC and the regulatory effect of SOX factors in the tumor immune microenvironment (TIME) of various cancers. For the first time, we analyze the association between the levels of SOX factors and that of immune components in HCC, providing clues to the pivotal role of SOX factors in the TIME of HCC. We also discuss the opportunities and challenges of targeting SOX factors for cancer. ABSTRACT: Sex determining region Y (SRY)-related high-mobility group (HMG) box (SOX) factors belong to an evolutionarily conserved family of transcription factors that play essential roles in cell fate decisions involving numerous developmental processes. In recent years, the significance of SOX factors in the initiation and progression of cancers has been gradually revealed, and they act as potential therapeutic targets for cancer. However, the research involving SOX factors is still preliminary, given that their effects in some leading-edge fields such as tumor immune microenvironment (TIME) remain obscure. More importantly, as a class of ‘undruggable’ molecules, targeting SOX factors still face considerable challenges in achieving clinical translation. Here, we mainly focus on the roles and regulatory mechanisms of SOX family members in hepatocellular carcinoma (HCC), one of the fatal human health burdens worldwide. We then detail the role of SOX members in remodeling TIME and analyze the association between SOX members and immune components in HCC for the first time. In addition, we emphasize several alternative strategies involved in the translational advances of SOX members in cancer. Finally, we discuss the alternative strategies of targeting SOX family for cancer and propose the opportunities and challenges they face based on the current accumulated studies and our understanding.