The identification of clinically druggable targets that restrict antitumour immunity is required to develop potential combination therapies. Using state-of-the-art single-cell multiomics in their newly established preclinical immune-checkpoint inhibitor (ICI)-resistant models and patients with HCC treated with anti-PD-1 therapy, Prof. Alfred S.L. Cheng’s research team identified class-I HDACs as key epigenetic drivers restricting the amplification of the antitumour immunity cycle, thereby contributing to the immune-refractory features of tumor microenvironment (TME). The successful conversion of the immune-excluded into an inflamed TME through epigenetic activation of a pyroptotic circuitry provides a mechanistic basis of a new combination immunotherapy with CXD101, a selective class-I HDAC inhibitor in patients with ICI-resistant HCC, which is currently tested in a Phase-II clinical trial in the Prince of Wales Hospital, Hong Kong (NCT05873244).

This research has been published in Gut:
https://gut.bmj.com/content/early/2024/11/01/gutjnl-2024-332281.info

Selective HDAC1/2/3 inhibition by CXD101 epigenetically overcomes ICI resistance by activating a self-reinforcing circuitry of IFNγ/STAT1 signalling and GSDME-mediated pyroptosis.

This work was primarily done by Dr. Yalin Tu (left) and Dr. Haoran Wu (right), former PhD students of Prof. Alfred Cheng (middle).