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<p>The benefit from immune checkpoint blockade (ICB) can be mitigated by the onset of immune-related adverse events (irAEs). The identification of checkpoints specific to irAEs could mitigate toxicity without antitumor efficacy trade-off. Here we integrated transcriptome and pharmacovigilance data to decipher the efficacy–toxicity equilibrium of ICB-regulated molecules and identified cytotoxic and regulatory T cell molecule (CRTAM) as an irAE checkpoint. <i>Crtam</i> knockout or T cell lineage-specific <i>Crtam</i> ablation impaired irAE induction in preclinical models. CRTAM⁺ T cells preferentially infiltrated normal tissues over tumors through the CRTAM–cell adhesion molecule 1 interaction and promoted interleukin 23-centered type 3 immunity. CRTAM inhibition preserved the ‘hot’ tumor microenvironment required for efficacy while mitigating toxicity in tumor-bearing irAE models. Quantification of the CRTAM–type 3 immune axis in blood samples enabled monitoring of irAEs in cohorts treated with ICB. Our study identifies CRTAM as a T cell checkpoint of irAEs, providing a potential target to uncouple efficacy from toxicity during immunotherapy.</p>

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CRTAM inhibition mitigates toxicity of immune checkpoint inhibitors without antitumor efficacy trade-off

  • 期刊论文

  • 发表日期：

    2026年3月5日

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  • Si-Cong Ma,
  • Zi-Xuan Rong,
  • Zi-Peng Xu,
  • Yan-Pei Zhang,
  • Kui-Mao Zhuang,
  • Hao Sun,
  • Chuan-Hui Cao,
  • Ze-Nan Wu,
  • Hai-Peng Zhang,
  • Qiang Zuo,
  • Jia-Run Lin,
  • Jia-Xin Cheng,
  • Hua-Ting Qu,
  • Duan-Duan Han,
  • Wei Wei,
  • Ke Liu,
  • Xiao-Ting Cai,
  • Ze-Qin Guo,
  • Xue Bai,
  • Li Liu,
  • De-Hua Wu,
  • Zhong-Yi Dong

摘要

The benefit from immune checkpoint blockade (ICB) can be mitigated by the onset of immune-related adverse events (irAEs). The identification of checkpoints specific to irAEs could mitigate toxicity without antitumor efficacy trade-off. Here we integrated transcriptome and pharmacovigilance data to decipher the efficacy–toxicity equilibrium of ICB-regulated molecules and identified cytotoxic and regulatory T cell molecule (CRTAM) as an irAE checkpoint. Crtam knockout or T cell lineage-specific Crtam ablation impaired irAE induction in preclinical models. CRTAM⁺ T cells preferentially infiltrated normal tissues over tumors through the CRTAM–cell adhesion molecule 1 interaction and promoted interleukin 23-centered type 3 immunity. CRTAM inhibition preserved the ‘hot’ tumor microenvironment required for efficacy while mitigating toxicity in tumor-bearing irAE models. Quantification of the CRTAM–type 3 immune axis in blood samples enabled monitoring of irAEs in cohorts treated with ICB. Our study identifies CRTAM as a T cell checkpoint of irAEs, providing a potential target to uncouple efficacy from toxicity during immunotherapy.