# Circular RNAs: roles in hepatocellular carcinoma immune regulation, implications in immunotherapy, and prospects for clinical translation

## TL;DR

This paper explores how circular RNAs influence the immune environment in liver cancer and how they could help improve immunotherapy treatments.

## Contribution

The paper uniquely integrates recent findings on how specific circRNAs regulate immune suppression and resistance in hepatocellular carcinoma.

## Key findings

- CircRNAs modulate immune cell function and polarization in hepatocellular carcinoma.
- CircRNAs interfere with key immune signaling pathways like NF-κB and Wnt/β-catenin.
- CircRNAs show potential as biomarkers and therapeutic targets for immunotherapy resistance.

## Abstract

Circular RNAs (circRNAs) are emerging as pivotal regulators within the tumor immune microenvironment (TIME) of hepatocellular carcinoma (HCC). Despite the transformative role of immunotherapy, its efficacy remains limited by primary and acquired resistance, a challenge not fully addressed by current research. This review uniquely synthesizes the latest evidence to delineate how specific circRNAs orchestrate immunosuppression in HCC through two interconnected axes: (1) by directly modulating the function and polarization of key immune cells (e.g., T cells, NK cells, macrophages), and (2) by interfering with core immune-related signaling pathways (e.g., NF-κB, MAPK, Wnt/β-catenin). We critically examine how these mechanisms collectively fuel immune evasion and confer resistance to immune checkpoint inhibitors. Moving beyond mechanism, we further explore the dual translational potential of circRNAs: as stable, minimally invasive diagnostic/prognostic biomarkers and as novel therapeutic targets via RNA interference or circRNA-based vaccine strategies. By connecting fundamental molecular insights to clinical challenges, this review provides a cohesive framework for understanding circRNA-driven immunomodulation in HCC and highlights promising avenues for overcoming immunotherapy resistance.