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<p>Despite the promise of immune checkpoint blockade (ICB), only a minority of non-small-cell lung cancer (NSCLC) patients achieve long-term benefits. In this study, we present a single-cell spatial transcriptomic landscape of NSCLC, revealing a previously uncharacterized link between elevated glutathione peroxidase 8 (Gpx8) and resistance to PD-1 blockade. Through CyTOF, CODEX, and ATAC-sequencing analyses, we demonstrate that Gpx8 knockout in both immunocompetent and humanized mouse models suppress tumor growth. This suppression is accompanied by increased infiltration of antitumor T lymphocytes, reduced enrichment of pro-tumorigenic myeloid cells, and the formation of tertiary lymphoid structures (TLS). Mechanistically, Gpx8 inhibits the activity of the RNA-binding protein Celf1(CUGBP Elav-like family member 1) through disulfide bonding between cysteine 79 of Gpx8 and cysteine 177 of Celf1. This interaction stabilizes CCAAT-enhancer-binding protein β (C/EBPβ) mRNA, promotes CSF1 secretion, and drives the recruitment of myeloid-derived suppressor cells (MDSCs) into the tumor microenvironment. Notably, resistance to anti-PD-1 treatment in Gpx8-expressing NSCLCs can be overcome through enforced expression of Celf1, CSF1R blockade, or a mimic peptide designed to disrupt the Gpx8-Celf1 interaction. Furthermore, anti-PD-1 or rCSF1 treatment activates C/EBPβ and upregulates Gpx8 transcription, establishing a Gpx8-C/EBPβ-CSF1 feedback loop that contributes to immune evasion. These findings provide new insights into the role of Gpx8 in modulating the tumor microenvironment and offer a potential framework for enhancing the sensitivity of NSCLC to PD-1 blockade therapy.</p>

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Targeting of Gpx8-CSF1 axis resets the immune milieu of lung tumor and overcomes resistance to anti-PD-1 therapy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月14日

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  • Heng Zhang,
  • Jialin Ma,
  • Meng Shi,
  • Liang Chen,
  • Yu-Fei Zhang,
  • Zhi Gao,
  • Zhuo-Ran Wang,
  • Biao Liu,
  • Wenwu Luo,
  • Huadong Pei,
  • Bin Wang,
  • Ling Chen,
  • Zhi-Gang Li,
  • Xing Feng,
  • Wen‑Yong Zhou

摘要

Despite the promise of immune checkpoint blockade (ICB), only a minority of non-small-cell lung cancer (NSCLC) patients achieve long-term benefits. In this study, we present a single-cell spatial transcriptomic landscape of NSCLC, revealing a previously uncharacterized link between elevated glutathione peroxidase 8 (Gpx8) and resistance to PD-1 blockade. Through CyTOF, CODEX, and ATAC-sequencing analyses, we demonstrate that Gpx8 knockout in both immunocompetent and humanized mouse models suppress tumor growth. This suppression is accompanied by increased infiltration of antitumor T lymphocytes, reduced enrichment of pro-tumorigenic myeloid cells, and the formation of tertiary lymphoid structures (TLS). Mechanistically, Gpx8 inhibits the activity of the RNA-binding protein Celf1(CUGBP Elav-like family member 1) through disulfide bonding between cysteine 79 of Gpx8 and cysteine 177 of Celf1. This interaction stabilizes CCAAT-enhancer-binding protein β (C/EBPβ) mRNA, promotes CSF1 secretion, and drives the recruitment of myeloid-derived suppressor cells (MDSCs) into the tumor microenvironment. Notably, resistance to anti-PD-1 treatment in Gpx8-expressing NSCLCs can be overcome through enforced expression of Celf1, CSF1R blockade, or a mimic peptide designed to disrupt the Gpx8-Celf1 interaction. Furthermore, anti-PD-1 or rCSF1 treatment activates C/EBPβ and upregulates Gpx8 transcription, establishing a Gpx8-C/EBPβ-CSF1 feedback loop that contributes to immune evasion. These findings provide new insights into the role of Gpx8 in modulating the tumor microenvironment and offer a potential framework for enhancing the sensitivity of NSCLC to PD-1 blockade therapy.