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Review
. 2022 Sep 2:12:958720.
doi: 10.3389/fonc.2022.958720. eCollection 2022.

Overcoming resistance to immune checkpoint inhibitors in hepatocellular carcinoma: Challenges and opportunities

Qingqing Xie  1 , Pengfei Zhang  1 , Yuanyuan Wang  2 , Wuxuan Mei  2 , Changchun Zeng  1
Affiliations
Review

Overcoming resistance to immune checkpoint inhibitors in hepatocellular carcinoma: Challenges and opportunities

Qingqing Xie et al. Front Oncol. .

Abstract

Hepatocellular carcinoma is one of the leading causes of cancer mortality globally, and its incidence is increasing. Immune checkpoint therapy has revolutionized the treatment of hepatocellular carcinoma over the past few years. However, only a limited proportion of patients with hepatocellular carcinoma respond to immunotherapy. Despite the significant breakthroughs, the molecular mechanisms that drive immune responses and evasion are largely unresolved. Predicting tumor response and resistance to immune checkpoint inhibitors is a significant challenge. In this review, we focus on the current research progress of immune checkpoint inhibitors in hepatocellular carcinoma. Importantly, this review highlights the underlying mechanisms of resistance to immune checkpoint inhibitors and summarizes potential strategies to overcome the resistance to immune checkpoint inhibitors in hepatocellular carcinoma.

Keywords: combination therapy; hepatocellular carcinoma; immune checkpoint inhibitors; mechanism; resistance.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Key mechanisms of immune checkpoint inhibitor resistance in hepatocellular carcinoma. (1) Inadequate, absence or alterations in the presentation or processing of tumor neoantigens; (2) alterations in oncogenic pathways, such as phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK), Janus kinase/signal transducer and activator of transcription (JAK/STAT),  Wnt/β-Catenin, and transforming growth factor beta (TGF-β) signaling pathways; (3 and 4) polarization toward an immunosuppressive microenvironment by reducing pro-inflammatory mediators and increasing anti-inflammatory mediators; (5) other novel immune checkpoint molecules, such as T-cell immunoglobulin and ITIM domain (TIGIT), lymphocyte activation gene-3 (LAG-3), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), B7 homolog 3 protein (B7-H3), B and T lymphocyte attenuator (BTLA), V-domain immunoglobulin suppressor of T cell activation (VISTA), and inducible T-cell costimulatory (ICOS).
Figure 2
Figure 2
Strategies to overcome ICI resistance.
See this image and copyright information in PMC

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