What question did this study set out to answer?

The study aims to understand how NSD2 influences HCC progression and immune evasion.

March 1, 2026Open Access

NSD2 inhibits the expression of PD-L1 via oxidative phosphorylation to control immune surveillance in hepatocellular carcinoma

Key Points

The study aims to understand how NSD2 influences HCC progression and immune evasion.
Utilized mouse and cell models to assess NSD2's effects on HCC
Employed RNA-seq and ChIP-seq to investigate downstream mechanisms
Examined orthotopic tumor models for in vivo analysis of NSD2 functions
Characterized NSD2 alterations in HCC patient specimens
Hepatocyte-specific NSD2 overexpression inhibits tumor cell proliferation in mice
NSD2 reduces oxidative phosphorylation (OXPHOS) and subsequently PD-L1 expression
Inhibition of OXPHOS leads to enhanced immune recognition of tumors
Patients with low NSD2 levels respond better to PD-L1 inhibitors

Abstract

Abstract Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death, and patients usually exhibit impaired immune function within the tumor environment. NSD2 is an H3K36 methyltransferase and has been considered a cancer-promoting factor. However, the role of NSD2 in the occurrence and development of HCC is still unclear. In this study, the effects of NSD2 on HCC were assessed by both mouse and cell models. RNA-seq, ChIP-seq, and orthotopic tumor models were employed to decipher the downstream mechanisms of NSD2 responsible for HCC development. NSD2 alterations were characterized in patients with HCC. Hepatocyte-specific NSD2 overexpression suppresses the proliferation of tumor cells in DEN-treated mice. Mechanistically, NSD2 inhibits OXPHOS by activating target genes (Camk2d and Prkce) transcription. Downregulation of OXPHOS, caused by overexpression of NSD2, inhibits the expression of PD-L1 and enhances immune recognition of tumors. What’s more, inhibition of OXPHOS suppresses the formation of HCC. Finally, patients with low expression of NSD2 have a better response to PD-L1 inhibitor treatment. These findings showed that NSD2 inhibits the progression of HCC by inhibiting the expression of PD-L1 through OXPHOS. Our results identify NSD2 as a tumor suppressor in the development of HCC.

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Cite This Study

Zhang et al. (Fri,) studied this question.

synapsesocial.com/papers/69a3d824ec16d51705d2eac9 https://doi.org/https://doi.org/10.1038/s41419-026-08490-x

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