Beyond gene signatures: a mechanism-based framework for cuproptosis susceptibility in non-small cell lung cancer at the metabolism–immunity interface
5 affiliations
- 1The First Affiliated Hospital of Dalian Medical University
- 2College of Health-Preservation and Wellness, Dalian Medical University
- 3College of Integrated Chinese and Western Medicine, Dalian Medical University
- 4Department of Vascular Surgery, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua Medicine, Tsinghua University
- 5Department of Oncology, The First Affiliated Hospital of Dalian Medical University
Abstract
Non-small cell lung cancer (NSCLC) has become a biomarker-driven disease, yet durable control remains limited by therapeutic resistance, metabolic heterogeneity, and incomplete predictors of response. Cuproptosis, a copper-dependent form of regulated cell death linked to mitochondrial respiration and lipoylated TCA-cycle proteins, offers a potential metabolic layer for patient stratification. However, the current NSCLC literature is dominated by cuproptosis-related gene scores, lncRNA models, and immune-association signatures. These studies are useful for hypothesis generation but rarely demonstrate copper flux, FDX1 dependence, lipoylated DLAT/DLST engagement, iron-sulfur cluster protein loss, or pathway-specific pharmacodynamics. We therefore organize the NSCLC literature using a mechanistic evidence matrix that separates transcriptomic association, copper-access enrichment, mitochondrial-dependence evidence, canonical target engagement, and clinical pharmacodynamic confirmation. Rather than proposing a new molecular subtype or diagnostic label, we conceptualize cuproptosis susceptibility as a continuous, mechanism-based construct defined by copper access, TCA/OXPHOS dependence, lipoylated substrate burden, detoxification capacity, and immune context. This framework reframes cuproptosis from universal copper toxicity to a conditional therapeutic vulnerability. Its clinical value will depend on biomarker-enriched trials with pharmacodynamic confirmation rather than retrospective gene signatures alone.
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BibTeX
@article{liang2026beyond,
title = {{Beyond gene signatures: a mechanism-based framework for cuproptosis susceptibility in non-small cell lung cancer at the metabolism–immunity interface}},
author = {Zhanhao Liang and Miao Cheng and Qinghao Song and Meizhu Zhou and Yiming Wang and Mingru Jiang and Shibiao Liu and Xutong Zhao and Yi Zhao},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1935389},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1935389/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Beyond gene signatures: a mechanism-based framework for cuproptosis susceptibility in non-small cell lung cancer at the metabolism–immunity interface
AU - Zhanhao Liang
AU - Miao Cheng
AU - Qinghao Song
AU - Meizhu Zhou
AU - Yiming Wang
AU - Mingru Jiang
AU - Shibiao Liu
AU - Xutong Zhao
AU - Yi Zhao
PY - 2026
DA - 2026/10/08
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1935389
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1935389/full
AB - Non-small cell lung cancer (NSCLC) has become a biomarker-driven disease, yet durable control remains limited by therapeutic resistance, metabolic heterogeneity, and incomplete predictors of response. Cuproptosis, a copper-dependent form of regulated cell death linked to mitochondrial respiration and lipoylated TCA-cycle proteins, offers a potential metabolic layer for patient stratification. However, the current NSCLC literature is dominated by cuproptosis-related gene scores, lncRNA models, and immune-association signatures. These studies are useful for hypothesis generation but rarely demonstrate copper flux, FDX1 dependence, lipoylated DLAT/DLST engagement, iron-sulfur cluster protein loss, or pathway-specific pharmacodynamics. We therefore organize the NSCLC literature using a mechanistic evidence matrix that separates transcriptomic association, copper-access enrichment, mitochondrial-dependence evidence, canonical target engagement, and clinical pharmacodynamic confirmation. Rather than proposing a new molecular subtype or diagnostic label, we conceptualize cuproptosis susceptibility as a continuous, mechanism-based construct defined by copper access, TCA/OXPHOS dependence, lipoylated substrate burden, detoxification capacity, and immune context. This framework reframes cuproptosis from universal copper toxicity to a conditional therapeutic vulnerability. Its clinical value will depend on biomarker-enriched trials with pharmacodynamic confirmation rather than retrospective gene signatures alone.
SN - 1664-3224
ER -