Cancer-associated fibroblasts in hepatocellular carcinoma: heterogeneity, mechanisms and therapeutic targets

Hepatocellular carcinoma (HCC) is one of the common malignant cancers worldwide. Although immunotherapy has improved the treatment outcome in HCC, a significant percentage of patients with advanced HCC still cannot benefit from immunotherapy. Therefore, developing new targets or combination therapeutic strategies to improve the efficacy of immunotherapy is urgently needed. A deeper understanding of the mechanisms underlying immune regulation may help in this regard. The tumor microenvironment (TME) consists of a diverse set of components modulating the efficacy of immunotherapy. Cancer-associated fibroblasts (CAFs) are critical components of the TME and can regulate both tumor and immune cells through secreted cytokines and exosomes that impact various signaling pathways in target cells. CAF-derived cytokines can also participate in extracellular matrix (ECM) remodeling, thereby impacting cancer progression and tumor responsiveness to immunotherapy among other effects. A thorough understanding of the phenotypic and functional profile dynamism of CAFs may lead the way for new treatment strategies and/or better treatment outcomes in HCC patients. In this review, we outline the biomarkers and functional heterogeneity of CAFs in HCC and elaborate on molecular mechanisms of CAFs, including anti-programmed cell death protein 1 (PD-1)/PD-ligand 1 (PD-L1) immunotherapy. We also examine current clinical implications of CAFs-related targets as potential therapeutic candidates in HCC.