Targeting Copper Death-Related Long Non-coding RNAs: A Novel Strategy to Overcome Immunotherapy Resistance in Liver Cancer

Abstract

Hepatocellular carcinoma (HCC) is characterized by a profoundly immunosuppressive microenvironment that fosters active peripheral immune tolerance, thereby severely compromising the efficacy of immune checkpoint inhibitors (ICIs). The recent characterization of cuproptosis—a mitochondrial metabolism-dependent cell death—unveils a novel mechanistic link between metabolic stress and the disruption of this tolerance. This review elucidates the pivotal role of copper death-related long non-coding RNAs (lncRNAs) (CRLs) as epigenetic orchestrators that navigate the delicate balance between immune surveillance and tolerance. We systematically delineate the multifaceted mechanisms through which CRLs drive immune evasion and active immunological tolerance. Rather than a passive failure of the immune system to recognize the tumor, CRLs orchestrate a programmatic remodeling of the microenvironment. This involves (1) actively recruiting immunosuppressive populations, such as regulatory T cells (Tregs) and M2 macrophages, to establish immune exclusion; (2) synergistically upregulating co-inhibitory checkpoints (e.g., PD-L1) to induce effector T cell exhaustion; and (3) functioning as "molecular brakes" on cuproptosis-induced immunogenicity. Crucially, we highlight the functional heterogeneity of CRLs, identifying a distinct subset of tumor-suppressive lncRNAs (e.g., LINC02362) capable of promoting immunogenic cell death (ICD) to break established peripheral tolerance. Furthermore, we critically evaluate translational strategies, ranging from composite biomarkers to intelligent nanodelivery systems designed to precisely modulate the CRL axis. By shifting the paradigm from "drug resistance" to "tolerance modulation," this review provides a strategic roadmap for harnessing CRL-targeted interventions to restore immune homeostasis and sensitize HCC to immunotherapy.