Immune checkpoint inhibitors in hepatocellular carcinoma therapy: resistance mechanisms, liver transplantation challenges and management strategies.

Abstract

Hepatocellular carcinoma (HCC) poses a significant clinical burden due to its aggressive nature, profound tumor heterogeneity, and limited therapeutic efficacy. While immune checkpoint inhibitors (ICIs) have revolutionized treatment paradigms and demonstrated considerable promise, the emergence of resistance mechanisms has posed a critical challenge in contemporary clinical oncology. The accelerated development of novel agents and innovative combination strategies has further complicated this resistance landscape. In this review, we present a unique and comprehensive analysis of ICI resistance mechanisms in HCC by integrating insights into primary resistance, acquired resistance, and host-related factors. Building upon this mechanistic framework, we explore emerging therapeutic strategies to overcome ICI resistance. Furthermore, we evaluate the dual role of ICIs in HCC management - serving as a neoadjuvant therapy for transplant candidates while simultaneously posing risks of post-transplant rejection. By bridging preclinical discoveries with clinical realities, this analysis aims to inform rational therapeutic design and optimize immuno-oncology trials for HCC patients.