Lysine‐specific demethylase 1 deletion reshapes tumour microenvironment to overcome acquired resistance to anti‐programmed death 1 therapy in liver cancer

作者：Chen Liang, Mu Ye, Lei Yu, Pengfei Zhang, Xiaojun Guo, Xian‐Long Meng, Haiying Zeng, Shu‐Yang Hu, Dao‐Han Zhang, Qi‐Man Sun, Ying‐Hao Shen, Jiabin Cai, Shuangqi Li, Zhen Chen, Ying–Hong Shi, Ai‐Wu Ke, Yujiang Geno Shi, Jian Zhou, Fan Jia, Feizhen Wu, Xiaoyong Huang, Guo‐Ming Shi, Zheng Tang, Jia‐Cheng Lu · 发表于：Clinical and Translational Medicine · 年份：2025 · DOI：10.1002/ctm2.70335 · 被引用次数：8 · 研究领域：Epigenetics and DNA Methylation、Macrophage Migration Inhibitory Factor、Immune cells in cancer

Abstract Background Immune checkpoint blockade, particularly targeting programmed death 1 (PD‐1) and programmed death ligand 1 (PD‐L1), shows promise in treating hepatocellular carcinoma (HCC). However, acquired resistance, especially in patients with ‘hot tumours’, limits sustained benefits. Lysine‐specific demethylase 1 (LSD1) plays a role in converting ‘cold tumours’ to ‘hot tumours’, but its involvement in PD‐1 inhibitor resistance in HCC is unclear. Methods LSD1 and PD‐L1 expression, along with CD8 + T cell infiltration, were assessed using immunohistochemistry in HCC tissues, correlating these markers with patient prognosis. The impact of LSD1 deletion on tumour cell proliferation and CD8 + T cell interactions was examined in vitro. Mouse models were used to study the combined effects of LSD1 inhibition and anti‐PD‐1 therapy on tumour growth and the tumour microenvironment (TME). The clinical relevance of LSD1, CD74 and effector CD8 + T cells was validated in advanced HCC patients treated with PD‐1 blockade. Results LSD1 overexpression in HCC patients correlated with reduced PD‐L1 expression, less CD8 + T cell infiltration and poorer prognosis. LSD1 deletion increased PD‐L1 expression, boosted effector CD8 + T cells in vitro and inhibited tumour growth in vivo. While anti‐PD‐1 monotherapy initially suppressed tumour growth, it led to relapse upon antibody withdrawal. In contrast, combining LSD1 inhibition with anti‐PD‐1 therapy effectively halted tumour growth and preve...