Interplay of Extracellular Vesicles and TLR4 Signaling in Hepatocellular Carcinoma Pathophysiology and Therapeutics

Abstract

Hepatocellular carcinoma (HCC) stands as a significant contributor to global cancer-related mortality. Chronic inflammation, often arising from diverse sources such as viral hepatitis, alcohol misuse, nonalcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH), profoundly influences HCC development. Within this context, the interplay of extracellular vesicles (EVs) gains prominence. EVs, encompassing exosomes and microvesicles, mediate cell-to-cell communication and cargo transfer, impacting various biological processes, including inflammation and cancer progression. Toll-like receptor 4 (TLR4), a key sentinel of the innate immune system, recognizes both pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), thereby triggering diverse signaling cascades and pro-inflammatory cytokine release. The intricate involvement of the TLR4 signaling pathway in chronic liver disease and HCC pathogenesis is discussed in this study. Moreover, we delve into the therapeutic potential of modulating the TLR4 pathway using EVs as novel therapeutic agents for HCC. This review underscores the multifaceted role of EVs in the context of HCC and proposes innovative avenues for targeted interventions against this formidable disease.

Inhibition of Hepatocellular Carcinoma by Endogenous Lipids: Induction of Pyroptosis by Geranylgeranoic Acid—A Comparison with Palmitic Acid and Retinoic Acid

“…GGA, as an endogenous lipid that selectively induces pyroptosis in tumor cells, occupies a slightly different position from saturated fatty acids. If tumor cells are considered foreign substances, further detailed research on factors determining the selectivity of tumor cells in the liver, such as analyzing changes in the expression levels of the TLR4 genes accompanying the development of liver cancer [92], is essential for understanding the tumor-selective action of GGA.…”

γδ T Cells: A Game Changer in the Future of Hepatocellular Carcinoma Immunotherapy

“…However, the effects of TKIs are context-dependent, influenced by dosing and specific TKI types. The complexity of immune responses within the TME has been thoroughly investigated [18,20]. Adding some levels of complexity to this intricate landscape, epigenetic mechanisms, such as DNA methylation, histone modifications, and non-coding RNAs, can also influence the development and progression of HCC by affecting the expression of genes involved in cell growth, differentiation, and apoptosis [105].…”

“…Comprising a complex interplay of immune cells, stromal elements, and signaling molecules, the TME significantly impacts the trajectory of HCC [18,66]. In this context, the immune TME often takes on an immunosuppressive profile, fostering conditions conducive to tumor growth and immune evasion [19,20].…”

“…This classification distinguishes HCC into three distinct classes: the inflamed class, the intermediate class, and the excluded class. Despite the promising avenue of immunotherapy, these findings emphasize the complexity of HCC's immune landscape [18][19][20][21][22][23][24] and the importance of tailoring novel treatments to its diverse molecular features [25].…”