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Background <p>Immune checkpoint inhibitors (ICIs) therapy have significantly improved survival in cancer patients. However, immune-related adverse events (irAEs) have emerged as a major challenge limiting its therapeutic efficacy. Recent studies have demonstrated that certain immune cell phenotypes and metabolites may be associated with the risk of irAEs. Nevertheless, the precise biological mechanisms for this association remain poorly understood.</p> Methods <p>Using genetic variants from large-scale genome-wide association studies (GWAS), we employed two-sample mendelian randomization (MR) to systematically investigate causal relationships among 731 immune cell phenotypes, 1400 metabolites, and the risk of both all-grade and high-grade irAEs. A two-step MR method was employed to further analyze the mediating effects of key immune cell phenotypes and metabolites in irAEs. The inverse-variance weighted (IVW) method served as the primary approach to assess causal relationships, while Cochran’s Q test, MR-Egger intercept test, MR-PRESSO, and leave-one-out analysis were employed to evaluate heterogeneity and horizontal pleiotropy.</p> Results <p>Our results found that metabolites mediate several causal pathways linking immune cell phenotypes to high-grade irAEs. Specifically, etiocholanolone glucuronide levels partially mediated the causal effect of CCR2 on monocyte in high-grade irAEs, with a mediation proportion of 0.0730 (95% CI 0.0032, 0.1428; <i>P</i> = 0.0403). Thymol sulfate levels partially mediated the causal effect of CD39 on monocyte in high-grade irAEs, with a mediation effect estimate of − 0.0321 (95% CI − 0.0621, − 0.0021; <i>P</i> = 0.0358). Our analysis identified putative associations for all-grade and high-grade irAEs with 10 and 11 immune cell phenotypes and causal relationships with 30 and 36 metabolites, respectively. Sensitivity analysis confirmed the robustness of these associations.</p> Conclusion <p>This study suggests causal relationships between immune cell phenotypes, metabolites and irAEs. Two metabolites that may act as potential mediating factors between immune cells and high-grade irAEs were identified. Of course, further investigation is warranted to validate these results.</p>

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The role of metabolites in the causal effect of immune cell phenotypes on immunotherapy toxicity risk

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月25日

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  • Meng Tang,
  • Fei Mu,
  • Zhen Yan,
  • Rui Gong,
  • Chen Cui,
  • KeXin Sun,
  • JinYi Zhao,
  • JingWen Wang

摘要

Background

Immune checkpoint inhibitors (ICIs) therapy have significantly improved survival in cancer patients. However, immune-related adverse events (irAEs) have emerged as a major challenge limiting its therapeutic efficacy. Recent studies have demonstrated that certain immune cell phenotypes and metabolites may be associated with the risk of irAEs. Nevertheless, the precise biological mechanisms for this association remain poorly understood.

Methods

Using genetic variants from large-scale genome-wide association studies (GWAS), we employed two-sample mendelian randomization (MR) to systematically investigate causal relationships among 731 immune cell phenotypes, 1400 metabolites, and the risk of both all-grade and high-grade irAEs. A two-step MR method was employed to further analyze the mediating effects of key immune cell phenotypes and metabolites in irAEs. The inverse-variance weighted (IVW) method served as the primary approach to assess causal relationships, while Cochran’s Q test, MR-Egger intercept test, MR-PRESSO, and leave-one-out analysis were employed to evaluate heterogeneity and horizontal pleiotropy.

Results

Our results found that metabolites mediate several causal pathways linking immune cell phenotypes to high-grade irAEs. Specifically, etiocholanolone glucuronide levels partially mediated the causal effect of CCR2 on monocyte in high-grade irAEs, with a mediation proportion of 0.0730 (95% CI 0.0032, 0.1428; P = 0.0403). Thymol sulfate levels partially mediated the causal effect of CD39 on monocyte in high-grade irAEs, with a mediation effect estimate of − 0.0321 (95% CI − 0.0621, − 0.0021; P = 0.0358). Our analysis identified putative associations for all-grade and high-grade irAEs with 10 and 11 immune cell phenotypes and causal relationships with 30 and 36 metabolites, respectively. Sensitivity analysis confirmed the robustness of these associations.

Conclusion

This study suggests causal relationships between immune cell phenotypes, metabolites and irAEs. Two metabolites that may act as potential mediating factors between immune cells and high-grade irAEs were identified. Of course, further investigation is warranted to validate these results.