Mechanisms of drug resistance in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is the most prevalent form of primary liver cancer, associated with high morbidity and mortality worldwide. Despite advancements in diagnostic methods and systemic treatments, including tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs), the development of drug resistance remains a significant challenge in HCC management. Traditional treatments such as surgical resection and transarterial chemoembolization offer limited efficacy, especially in advanced stages. Although novel therapies like lenvatinib, sorafenib, regorafenib, and ICIs have shown promise, their effectiveness is often hindered by primary and acquired resistance, leading to poor long-term survival outcomes. This review focuses on the molecular mechanisms underlying resistance to targeted therapies and immunotherapies in HCC. Key factors contributing to resistance include alterations in the tumor microenvironment (TME), immune evasion, hypoxia, changes in cellular metabolism, and genetic mutations. Additionally, molecular players such as ferroptosis, autophagy, apoptosis, endoplasmic reticulum stress, ABC transporters, and non-coding RNAs(ncRNAs) are discussed as contributors to drug resistance. Understanding these mechanisms is critical for the development of novel therapeutic strategies aimed at overcoming resistance, improving patient outcomes, and ultimately enhancing survival rates in HCC patients.

Keywords: Drug resistance; Hepatocellular carcinoma; Immune checkpoint inhibitors; Targeted therapy; Tumor microenvironment.

Fig. 1

Mechanisms of immune evasion promoted by Tregs and MDSCs via immune checkpoints and inhibitory cytokines This figure illustrates how Tregs and MDSCs promote immune evasion by inhibiting effector T cell activity through multiple pathways in the TME. Tregs interact with antigen-presenting cells via CTLA-4 and secrete IL-10 and TGF-β to suppress effector T cells. MDSCs further inhibit effector T cells through the PD-1/PD-L1 pathway, enhancing tumor immune evasion. The function of NK cells is also suppressed, reducing the clearance of tumor cells

Fig. 2

TAMs promote tumor immune evasion and drug resistance via the JAK/STAT3 signaling pathway. This figure illustrates how tumor-associated macrophages (TAMs) promote immune evasion and drug resistance by secreting IL-10 and VEGF, which activate the JAK/STAT3 signaling pathway in tumor cells. IL-10 activates the JAK/STAT3 pathway, inducing the expression of survival and angiogenesis-promoting genes such as Cyclin D1, Bcl-2, Mcl-1, and VEGF, thereby enhancing tumor cell survival, proliferation, and immune evasion. VEGF secretion further promotes tumor angiogenesis, supporting tumor growth