Targeting TIME in advanced hepatocellular carcinoma: Mechanisms of drug resistance and treatment strategies

Hepatocellular carcinoma (HCC) is the predominant form of primary liver cancer. While early-stage HCC can be effectively managed with surgical resection and other interventions, treatment options for advanced HCC are limited. Current systemic treatments for advanced HCC include VEGF-targeted tyrosine kinase inhibitors (Sorafenib, Lenvatinib), and the combination therapy of anti PD-1/PD-L1 and anti VEGF (Atezolizumab plus Bevacizumab, Camrelizumab plus Rivoceranib). However, the lack of response to these drugs and the emergence of acquired drug resistance significantly impairs their efficacy. Numerous studies have demonstrated that the tumor immune microenvironment (TIME) plays a crucial role in modulating the response to these therapies. Various immune cells and their secreted factors within the TIME play a pivotal role in the emergence of secondary drug resistance in HCC. This article reviews the mechanism of TIME promoting drug resistance, discusses the influence of current systemic HCC treatment drugs on TIME, and evaluates how these TIME changes affect the efficacy of treatment. A deeper understanding of the interaction between TIME and systemic treatment drugs may be beneficial to enhance the treatment effect, mitigate drug resistance of advanced HCC, and ultimately improve the prognosis of patients.