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Background <p>Ferroptosis has emerged as a pivotal mechanism in cancer surveillance, particularly in determining the efficacy of immunotherapy. However, the precise genetic switches that regulate ferroptosis sensitivity within specific immune cell lineages remain poorly characterized due to the resolution limits of bulk tissue analysis.</p> Methods <p>To address this, we constructed a high-resolution genetic map of ferroptosis in non-small cell lung cancer (NSCLC). We applied a multi-stage integrative framework, harmonizing single-cell expression quantitative trait loci (sc-eQTL) from 14 immune cell populations with large-scale genomic data from the FinnGen cohort (N = 385,195).</p> Results <p>The primary cis-eQTL MR screen identified 39 nominal ferroptosis-related candidate genes associated with NSCLC risk. In the cell-state-specific analysis, 21 evaluable gene-cell MR tests yielded seven nominal associations, of which five remained significant after Benjamini–Hochberg correction. GSTM1 showed the strongest protective signal in naive CD8+ T cells (OR = 0.595, 95% CI 0.452–0.784; P = 2.17 × 10<sup>−4</sup>; q = 0.0027), with an additional FDR-significant effect in naive CD4+ T cells. MAPK3 showed state-dependent effects, with protective associations in naive CD4+ T cells and naive B cells, but a risk-direction association in effector CD4+ T cells. Colocalization analysis did not provide strong evidence for a shared causal variant at the GSTM1 locus (maximum PP.H4 = 0.12), and was therefore interpreted as a sensitivity analysis rather than independent causal confirmation.</p> Conclusions <p>These findings prioritize GSTM1 and MAPK3 as cell-state-dependent ferroptosis-related candidates in NSCLC immunity. The results support a testable model in which GSTM1 may help preserve T-cell redox fitness, but external ancestry-diverse replication and in vitro functional validation are required before therapeutic translation.</p>

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Single-cell genetic architecture prioritizes GSTM1 as a candidate regulator of T-cell ferroptosis in NSCLC

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月30日

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  • Shouyong Xiao,
  • Siyun Wu,
  • Xianfeng Shao,
  • Ming Chao,
  • Qiubo Huang,
  • Guangjian Li,
  • Lianhua Ye

摘要

Background

Ferroptosis has emerged as a pivotal mechanism in cancer surveillance, particularly in determining the efficacy of immunotherapy. However, the precise genetic switches that regulate ferroptosis sensitivity within specific immune cell lineages remain poorly characterized due to the resolution limits of bulk tissue analysis.

Methods

To address this, we constructed a high-resolution genetic map of ferroptosis in non-small cell lung cancer (NSCLC). We applied a multi-stage integrative framework, harmonizing single-cell expression quantitative trait loci (sc-eQTL) from 14 immune cell populations with large-scale genomic data from the FinnGen cohort (N = 385,195).

Results

The primary cis-eQTL MR screen identified 39 nominal ferroptosis-related candidate genes associated with NSCLC risk. In the cell-state-specific analysis, 21 evaluable gene-cell MR tests yielded seven nominal associations, of which five remained significant after Benjamini–Hochberg correction. GSTM1 showed the strongest protective signal in naive CD8+ T cells (OR = 0.595, 95% CI 0.452–0.784; P = 2.17 × 10−4; q = 0.0027), with an additional FDR-significant effect in naive CD4+ T cells. MAPK3 showed state-dependent effects, with protective associations in naive CD4+ T cells and naive B cells, but a risk-direction association in effector CD4+ T cells. Colocalization analysis did not provide strong evidence for a shared causal variant at the GSTM1 locus (maximum PP.H4 = 0.12), and was therefore interpreted as a sensitivity analysis rather than independent causal confirmation.

Conclusions

These findings prioritize GSTM1 and MAPK3 as cell-state-dependent ferroptosis-related candidates in NSCLC immunity. The results support a testable model in which GSTM1 may help preserve T-cell redox fitness, but external ancestry-diverse replication and in vitro functional validation are required before therapeutic translation.