Lysine-specific demethylase 1 deletion reshapes tumour microenvironment to overcome acquired resistance to anti-programmed death 1 therapy in liver 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 prevented relapse, likely through TME remodelling, enhanced CD8⁺ T cell activity and improved CD74-mediated antigen presentation. Clinically, low LSD1 expression was associated with better response to anti-PD-1 therapy.

Conclusion: LSD1 deletion reshapes the TME, enhances CD8⁺ T cell function and prevents acquired resistance to anti-PD-1 therapy in HCC. The combination of LSD1 inhibitors and PD-1 blockade offers a promising strategy for overcoming resistance in advanced HCC.

Keywords

acquired resistance / hepatocellular carcinoma / immune checkpoint blockade / lysine-specific demethylase 1 / programmed death ligand 1 / programmed death protein 1 / tumour microenvironment

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2025 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.