中医药逆转肝细胞癌仑伐替尼获得性耐药研究进展OA

Hepatocellular carcinoma(HCC)is a malignant tumor with high global mortality.Lenvatinib,as a first-line targeted agent for advanced HCC,often faces clinical limitations due to acquired resistance.The resistance mechanisms are complex and diverse,involving compensatory activation of key signaling pathways,tumor microenvironment remodeling,metabolic reprogramming,non-coding RNA regulation,epigenetic modifications,and cancer stem cell maintenance,which together form a complex resistance network and severely compromise therapeutic efficacy.In recent years,traditional Chinese medicine(TCM)has shown promising prospects in reversing lenvatinib resistance due to its multi-targeting and holistic regulatory properties.Numerous studies have confirmed that TCM monomers and compound formulas can interfere with resistance-related signal transduction and alleviate adverse drug reactions,playing a unique role in"reducing toxicity and enhancing efficacy."The combination of TCM and Western medicine has become an important research direction for advanced HCC.This review focuses on the core mechanisms of lenvatinib resistance,emphasizing the roles of aberrant signaling pathways,non-coding RNA regulation,immune dysregulation in the tumor microenvironment,maintenance of cancer stem cell properties,and epigenetic modifications in resistance development.Furthermore,it summarizes the research progress of TCM monomers and compound formulas in restoring the sensitivity of HCC cells to lenvatinib through multiple pathways,including inhibiting compensatory pathways,interfering with the epitranscriptomic regulation,reversing metabolic reprogramming,and remodeling the immune microenvironment.Current research still has limitations:most mechanistic explorations are confined to single pathways,with insufficient analysis of crosstalk and synergistic effects among multiple mechanisms;high-quality clinical translational research is lacking,particularly large-scale,prospective evidence;and studies on the specific resistance characteristics of hepatitis B-associated HCC in China remain inadequate.Future efforts should focus on establishing resistance models of hepatitis B-associated HCC,deepening the multi-component and multi-target mechanistic analysis of TCM compound formulas,exploring novel combination therapies of TCM with targeted therapy and immunotherapy,investigating the triple combination strategy of"lenvatinib plus immune checkpoint inhibitors plus TCM compound formulas"to elucidate the molecular mechanisms underlying their synergistic effects,and conducting prospective clinical studies to improve the evidence-based medical system tailored to China's clinical practice,thereby providing theoretical foundations and new insights for overcoming lenvatinib resistance and optimizing comprehensive treatment for advanced HCC.