-Professor Shih-Hsien Hsu's Research Team, Graduate Institute of Medicine, Kaohsiung Medical University-

Liver cancer remains one of the leading causes of cancer-related deaths worldwide. Although immunotherapy has improved treatment outcomes for some patients, many tumors can still evade immune surveillance, limiting therapeutic success. Understanding how cancer cells escape the immune system has therefore become a major focus of cancer research.

A recent study published in Experimental Hematology & Oncology identified a previously unrecognized mechanism that enables liver cancer cells to remodel their immune microenvironment. The researchers discovered that the gene ISX cooperates with the transcription factor TWIST1 to activate CD47 and inflammasome-related signaling. CD47 is widely known as the "Don't Eat Me" signal because it prevents macrophages—the immune cells responsible for eliminating abnormal cells—from recognizing and engulfing cancer cells. As a result, tumors create an environment that favors immune escape and continued growth.

By analyzing clinical samples from hundreds of liver cancer patients, the study further demonstrated that high expression of both ISX and CD47 is associated with poorer prognosis and shorter overall survival, highlighting their potential as prognostic biomarkers. The researchers also found that ISX promotes the polarization of tumor-associated macrophages from the tumor-fighting M1 subtype to the tumor-promoting M2 subtype, further suppressing anti-tumor immunity.

The major breakthrough of this work is the identification of the ISX–TWIST1–CD47–inflammasome signaling axis, providing new insight into how liver cancer actively reshapes its immune microenvironment rather than simply growing uncontrollably. This discovery advances our understanding of tumor immune regulation and opens new avenues for cancer research.

Looking ahead, this pathway may provide new therapeutic opportunities by combining anti-CD47 antibodies, immune checkpoint inhibitors, or other targeted therapies to improve the effectiveness of current immunotherapies. In addition, ISX- and CD47-related molecules have strong potential to serve as biomarkers for diagnosis, prognosis, and treatment response prediction, supporting the development of precision medicine. As liver cancer becomes increasingly associated with metabolic disorders such as fatty liver disease, these findings may also accelerate interdisciplinary collaborations, translational research, and the development of next-generation cancer therapies.

Figure 1: The transcription factor ISX is a key regulator of chronic inflammation and hepatocarcinogenesis (provided by Professor Hsu Shih-Hsien).

Wang LT, Lin MH, Li YC, Wang SN, Chai CY, Hsu JM, Chiou SS, Chiou HC, Huang SK, Hung MC, Hsu SH*（許世賢）. ISX-TWIST1 reprograms CD47-inflammasome signaling to reshape the immune microenvironment in liver cancer. Exp Hematol Oncol. 2026 May 4;15(1):60. (SCIE, IF₂₀₂₅: 17.5, 5/103=4.85% in HEMATOLOGY)