Interactions in hepatic tumor microenvironment: Potential targets and modulations for effective therapy

The hepatic tumor microenvironment (TME) exhibits complex interactions among diverse cellular components. Hepatocellular carcinoma cells actively communicate with the surrounding stroma and extracellular matrix (ECM). These interactions create an immunosuppressive and pro-tumorigenic environment. Cancer-associated fibroblasts (CAFs) are able to liberate several factors that promote tumor progression and ECM. Metabolic reprogramming and hypoxia in TME influence tumor growth and response to antitumor drugs through bidirectional signaling between tumor and stromal cells. Similarly, activated stellate cells contribute to matrix remodeling and tumor expansion. Tumor-associated macrophages (TAMs), regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and Kupffer cells can support immune evasion. Recent studies have identified key molecular mediators in these cellular networks. Several targeting strategies show promise in preclinical models. These include immune checkpoint inhibitors (ICIs), immunomodulators, stromal cell modulators, and matrix-degrading agents. However, the effectiveness of conventional therapies remains limited by microenvironmental barriers. Recent progress in the knowledge of TME, nanoparticles, immunomodulators, and even natural-derived molecules with immunoregulatory effects has shown promise in preclinical studies. This review aims to analyze critical interactions within the hepatic TME and evaluate emerging therapeutic approaches that target these interactions for improved treatment outcomes.