Work

Long non-coding RNA-mediated stress adaptation and immune remodeling in non-small cell lung cancer: molecular mechanisms and therapeutic implications

Year: 2026

Type: article

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.

Source: Frontiers in Immunology

DOI: 10.3389/fimmu.2026.1982129