Exosome-mediated Crosstalk in the Tumor Immune Microenvironment: Critical Drivers of Hepatocellular Carcinoma Progression

Abstract

Hepatocellular carcinoma (HCC) is a significant global health issue, ranking as the sixth most prevalent malignancy and the fourth leading cause of cancer-related mortality worldwide. Despite advancements in therapeutic strategies, mortality rates for HCC remain high. The tumor immune microenvironment (TIME) plays a vital role in HCC progression by influencing tumor cell survival and growth. Recent studies highlight the essential role of exosomes in mediating intercellular communication within the TIME, particularly in interactions among tumor cells, immune cells, and fibroblasts. These interactions drive critical aspects of tumor development, including immune escape, angiogenesis, drug resistance, and metastasis. A detailed understanding of the molecular mechanisms by which exosomes modulate the TIME is essential for developing targeted therapies. This review systematically evaluated the roles and regulatory mechanisms of exosomes within the TIME of HCC, examining the impact of both HCC-derived and non-HCC-derived exosomes on various cellular components within the TIME. It emphasized their regulatory effects on cell phenotypes and functions, as well as their roles in HCC progression. The review also explored the potential applications of exosome-based immunotherapies, offering new insights into improving therapeutic strategies for HCC.

Keywords: Cancer therapy; Exosome; Hepatocellular carcinoma; Signal Transduction; Tumor Escape; Tumor immune environment.

Fig. 1. The process of exosome biogenesis, release, and uptake.

The source and recipient cells of exosomes can be any cells within the tumor immune microenvironment. (A) Various mechanisms initiate the inward budding of the plasma membrane, leading to the formation of early endosomes. (B) These early endosomes then sequester a diverse array of cargo, including proteins, lipids, RNA, and DNA, into ILVs, forming MVBs. (C) MVBs dynamically interact with other cellular organelles and compartments, including the TGN and the ER. These interactions regulate the generation of MVBs and influence the molecular contents of ILVs. (D) With the maturation of MVBs, they are capable of either fusing with lysosomes for degradation or with the plasma membrane to release their intraluminal vesicles as exosomes. (E) Following their release, exosomes can impact recipient cells via receptor-dependent interactions, endocytosis, or direct fusion with the recipient cell membrane. ILVs, intraluminal vesicles; MVBs, multivesicular bodies; TGN, trans-Golgi network; ER, endoplasmic reticulum; HCC, hepatocellular carcinoma; CAF, cancer-associated fibroblast; NK, natural killer cell; DC, dendritic cell.

Fig. 2. The role of HCC-derived exosomes in mediating crosstalk within the tumor immune microenvironment and promoting HCC progression.

HCC cells secrete diverse exosomes that actively remodel the tumor immune microenvironment, influencing both immune and stromal cell functions. This exosome-mediated crosstalk enables tumor cells to evade immune surveillance, thereby supporting tumor cell proliferation and metastasis. Furthermore, damaged liver cells release exosomes that activate quiescent HSCs, driving excessive extracellular matrix synthesis. This pathway exacerbates the progression of MAFLD and liver fibrosis, establishing a pathological foundation for HCC. HCC, hepatocellular carcinoma; MAFLD, metabolic dysfunction-associated fatty liver disease; HSCs, hepatic stellate cells; DC, dendritic cell; NK, natural killer cell; ↑, upregulation; ↓, downregulation.

Fig. 3. The roles of non-HCC-derived exosomes in mediating crosstalk within the tumor immune microenvironment and HCC development.

HCC, hepatocellular carcinoma. HSCs, Hepatic stellate cells; CAF, cancer-associated fibroblast; MSC, mesenchymal stem cells; ↑, upregulation; ↓, downregulation.