Long non-coding RNA-mediated stress adaptation and immune remodeling in non-small cell lung cancer: molecular mechanisms and therapeutic implications
- 1School of Forensic Medicine, Henan Medical University
- 2Xinxiang Engineering Technology Research Center of Immune Checkpoint Drug for Liver-Intestinal Tumors, Henan Medical University
- 3School of Basic Medical Sciences, Henan Medical University
Abstract
Non-small cell lung cancer (NSCLC) remains the predominant subtype of lung cancer and a leading cause of cancer-related mortality worldwide. Therapeutic failure is largely driven by intratumoral heterogeneity, dynamic tumor microenvironmental stresses, and adaptive drug resistance. Unlike previous reviews focusing on isolated lncRNA–target axes, this review proposes an integrated conceptual framework emphasizing that four major classes of tumor-associated stresses are highly interconnected through a cross-stress compensatory network. Within this framework, lncRNAs serve as central yet functionally stratified regulatory nodes bridging stress sensing and adaptive reprogramming. We propose a functional continuum rather than a fixed binary classification: stress-sensing and downstream effector lncRNAs represent relative positions along a stress-input-to-adaptive-output axis, and the same lncRNA may switch or combine these roles depending on cell type, genetic background, stress intensity, and treatment context. We systematically illustrate how stress-responsive lncRNAs reshape metabolic reprogramming, redox homeostasis, ferroptosis susceptibility, immune evasion, autophagy, DNA-damage repair, and therapeutic resistance. We further show that these four stress conditions do not operate in isolation; rather, metabolites, ROS, hypoxia-responsive signaling, and intercellular communication generate reciprocal feedback and cross-compensation that together sustain tumor survival under sustained pressure. Beyond mechanistic integration, we discuss the translational prospects of stress-related lncRNAs as diagnostic and prognostic biomarkers, therapeutic targets, and mediators for mechanism-based combination therapies. However, it is critical to note that no lncRNA-targeting therapeutic agent has yet entered clinical trials for NSCLC, and the path from bench to bedside remains constrained by delivery challenges, model fidelity limitations, and insufficient standardization of clinical assays. Comprehensive dissection of lncRNA-mediated stress-adaptation networks will deepen our understanding of NSCLC pathogenesis and facilitate the development of precision medicine strategies.
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BibTeX
@article{shang2026long,
title = {{Long non-coding RNA-mediated stress adaptation and immune remodeling in non-small cell lung cancer: molecular mechanisms and therapeutic implications}},
author = {Fuyao Shang and Yiqiu Zhang and Qingyuan Zhou and Mengxiang Zhu and Fengyuan He and Mengxiang Li and Tiesuo Zhao and Sheng Guo and Jiateng Zhong and Zhijun Yang and Fei Tu},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1982129},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1982129/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Long non-coding RNA-mediated stress adaptation and immune remodeling in non-small cell lung cancer: molecular mechanisms and therapeutic implications
AU - Fuyao Shang
AU - Yiqiu Zhang
AU - Qingyuan Zhou
AU - Mengxiang Zhu
AU - Fengyuan He
AU - Mengxiang Li
AU - Tiesuo Zhao
AU - Sheng Guo
AU - Jiateng Zhong
AU - Zhijun Yang
AU - Fei Tu
PY - 2026
DA - 2026/10/22
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1982129
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1982129/full
AB - Non-small cell lung cancer (NSCLC) remains the predominant subtype of lung cancer and a leading cause of cancer-related mortality worldwide. Therapeutic failure is largely driven by intratumoral heterogeneity, dynamic tumor microenvironmental stresses, and adaptive drug resistance. Unlike previous reviews focusing on isolated lncRNA–target axes, this review proposes an integrated conceptual framework emphasizing that four major classes of tumor-associated stresses are highly interconnected through a cross-stress compensatory network. Within this framework, lncRNAs serve as central yet functionally stratified regulatory nodes bridging stress sensing and adaptive reprogramming. We propose a functional continuum rather than a fixed binary classification: stress-sensing and downstream effector lncRNAs represent relative positions along a stress-input-to-adaptive-output axis, and the same lncRNA may switch or combine these roles depending on cell type, genetic background, stress intensity, and treatment context. We systematically illustrate how stress-responsive lncRNAs reshape metabolic reprogramming, redox homeostasis, ferroptosis susceptibility, immune evasion, autophagy, DNA-damage repair, and therapeutic resistance. We further show that these four stress conditions do not operate in isolation; rather, metabolites, ROS, hypoxia-responsive signaling, and intercellular communication generate reciprocal feedback and cross-compensation that together sustain tumor survival under sustained pressure. Beyond mechanistic integration, we discuss the translational prospects of stress-related lncRNAs as diagnostic and prognostic biomarkers, therapeutic targets, and mediators for mechanism-based combination therapies. However, it is critical to note that no lncRNA-targeting therapeutic agent has yet entered clinical trials for NSCLC, and the path from bench to bedside remains constrained by delivery challenges, model fidelity limitations, and insufficient standardization of clinical assays. Comprehensive dissection of lncRNA-mediated stress-adaptation networks will deepen our understanding of NSCLC pathogenesis and facilitate the development of precision medicine strategies.
SN - 1664-3224
ER -