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<p>Patients with impaired tumour-specific major histocompatibility complex class I (tsMHC-I<sup>impaired</sup>) often fail to respond to immune checkpoint blockade (ICB), presenting a major clinical challenge. However, through our multicentre investigation, we observed that a subset of patients with tsMHC-I<sup>impaired</sup> remains responsive to ICB, a phenomenon that has not been fully explained. Here we identify a COTL1<sup>high</sup> natural killer (NK) subset that mediates ICB responsiveness in these patients. Mechanistically, PD-L1<sup>+</sup> macrophages coexpress GITRL and engage GITR on COTL1<sup>high</sup> NK cells, whereas PD-L1 blockade relieves the PD-1-mediated inhibition of GITR signalling and promotes NK cell activation. Activated COTL1<sup>high</sup> NK cells enhance immunological synapse stability and IFN-γ production via a metabolic–H3K27ac–RBPJ axis, thereby upregulating tsMHC-I expression and reinforcing adaptive anti-tumour immunity. Notably, GITR activation significantly enhances the sensitivity to anti-PD-L1 therapy in tsMHC-I<sup>impaired</sup> models. Our findings identify COTL1<sup>high</sup> NK cells as key determinants of ICB responsiveness and highlight the GITRL–GITR axis as a promising therapeutic target for tsMHC-I<sup>impaired</sup> tumours.</p>

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Reinvigorating COTL1high NK cells via GITR signalling overcomes immune checkpoint blockade resistance in tsMHC-I-impaired tumours

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月30日

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  • Wenhua You,
  • Chupeng Hu,
  • Yuhan Zhang,
  • Yedi Huang,
  • Jianzhou Yuan,
  • Cai-Yuan Wu,
  • Deyuan Kong,
  • Mengya Zhao,
  • Yueqing Han,
  • Songmao Li,
  • Ruimin Shan,
  • Jinying Lu,
  • Ming Cheng,
  • Qing Li,
  • Bin Yao,
  • Xiao-Fang Yu,
  • Qing Xia,
  • Wei Chong,
  • Dong-Ming Kuang,
  • Yun Chen

摘要

Patients with impaired tumour-specific major histocompatibility complex class I (tsMHC-Iimpaired) often fail to respond to immune checkpoint blockade (ICB), presenting a major clinical challenge. However, through our multicentre investigation, we observed that a subset of patients with tsMHC-Iimpaired remains responsive to ICB, a phenomenon that has not been fully explained. Here we identify a COTL1high natural killer (NK) subset that mediates ICB responsiveness in these patients. Mechanistically, PD-L1+ macrophages coexpress GITRL and engage GITR on COTL1high NK cells, whereas PD-L1 blockade relieves the PD-1-mediated inhibition of GITR signalling and promotes NK cell activation. Activated COTL1high NK cells enhance immunological synapse stability and IFN-γ production via a metabolic–H3K27ac–RBPJ axis, thereby upregulating tsMHC-I expression and reinforcing adaptive anti-tumour immunity. Notably, GITR activation significantly enhances the sensitivity to anti-PD-L1 therapy in tsMHC-Iimpaired models. Our findings identify COTL1high NK cells as key determinants of ICB responsiveness and highlight the GITRL–GITR axis as a promising therapeutic target for tsMHC-Iimpaired tumours.