# Targeting copper death-related long non-coding RNAs: a novel strategy to overcome immunotherapy resistance in liver cancer

## TL;DR

This paper explores how copper death-related long non-coding RNAs (CRLs) contribute to immune tolerance in liver cancer and suggests targeting them as a new strategy to improve immunotherapy.

## Contribution

The paper introduces CRLs as novel epigenetic regulators of immune tolerance and proposes targeting them to overcome immunotherapy resistance in hepatocellular carcinoma.

## Key findings

- CRLs actively recruit immunosuppressive cells like Tregs and M2 macrophages to establish immune exclusion.
- CRLs synergistically upregulate co-inhibitory checkpoints such as PD-L1 to induce T cell exhaustion.
- Some CRLs, like LINC02362, promote immunogenic cell death to break peripheral tolerance.

## 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.