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<p>Cancer cells frequently rewire their metabolism to support proliferation and evade immune surveillance, but little is known about metabolic targets that could increase immune surveillance. Here we show a specific means of mitochondrial respiratory complex I (CI) inhibition that improves tumor immunogenicity and sensitivity to immune checkpoint blockade (ICB). Targeted genetic deletion of either <i>Ndufs4</i> or <i>Ndufs6</i>, but not other CI subunits, induces an immune-dependent growth attenuation in melanoma and breast cancer models. We show that deletion of <i>Ndufs4</i> induces expression of the major histocompatibility complex (MHC) class I co-activator <i>Nlrc5</i> and antigen presentation machinery components, most notably <i>H2-K1</i>. This induction of MHC-related genes is driven by a pyruvate dehydrogenase-dependent accumulation of mitochondrial acetyl-CoA, which leads to an increase in histone H3K27 acetylation within the <i>Nlrc5</i> and <i>H2-K1</i> promoters. Taken together, this work shows that selective CI inhibition restricts tumor growth and that specific targeting of <i>Ndufs4</i> or <i>Ndufs6</i> increases T cell surveillance and ICB responsiveness.</p>

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Selective deficiency of mitochondrial respiratory complex I subunits Ndufs4/6 causes tumor immunogenicity

  • 期刊论文

  • 发表日期：

    2025年1月17日

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  • Jiaxin Liang,
  • Tevis Vitale,
  • Xixi Zhang,
  • Thomas D. Jackson,
  • Deyang Yu,
  • Mark Jedrychowski,
  • Steve P. Gygi,
  • Hans R. Widlund,
  • Kai W. Wucherpfennig,
  • Pere Puigserver

摘要

Cancer cells frequently rewire their metabolism to support proliferation and evade immune surveillance, but little is known about metabolic targets that could increase immune surveillance. Here we show a specific means of mitochondrial respiratory complex I (CI) inhibition that improves tumor immunogenicity and sensitivity to immune checkpoint blockade (ICB). Targeted genetic deletion of either Ndufs4 or Ndufs6, but not other CI subunits, induces an immune-dependent growth attenuation in melanoma and breast cancer models. We show that deletion of Ndufs4 induces expression of the major histocompatibility complex (MHC) class I co-activator Nlrc5 and antigen presentation machinery components, most notably H2-K1. This induction of MHC-related genes is driven by a pyruvate dehydrogenase-dependent accumulation of mitochondrial acetyl-CoA, which leads to an increase in histone H3K27 acetylation within the Nlrc5 and H2-K1 promoters. Taken together, this work shows that selective CI inhibition restricts tumor growth and that specific targeting of Ndufs4 or Ndufs6 increases T cell surveillance and ICB responsiveness.