Interactions and communications in hepatocellular carcinoma: Potential targets for chemo/radiosensitization

Hepatocellular carcinoma (HCC) is known as one of the poor-prognosis malignancies. HCC stroma contains a complex ecosystem. Malignant cells in HCC orchestrate intricate cellular interactions and signaling networks to maintain expansion. The tumor microenvironment (TME) in HCC contains various cells with remarkable plasticity, enabling cancer cells to withstand various therapeutic interventions through multiple resistance mechanisms. Upon exposure to chemotherapy or radiation, HCC cells activate sophisticated DNA damage response (DDR) pathways, cell-cycle checkpoints, and immune-evasion mechanisms. Beyond these mechanisms, HCC employs diverse pro-survival strategies, particularly through the upregulation of anti-apoptotic, angiogenesis, and tyrosine kinases, as well as autophagy modulation. The immunosuppressive landscape of HCC further compounds therapeutic resistance, where cancer-associated fibroblasts (CAFs) serve as key architects in restructuring the stromal compartment. Myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), neutrophils, and macrophages collectively establish an immunologically "cold" environment that shields tumor cells from both therapeutic agents and immune surveillance. These cellular interactions occur through an elaborate network of cytokines, chemokines, and metabolic intermediates. This review aims to dissect these multifaceted interactions within the HCC microenvironment and explore emerging strategies to disrupt these communication networks, potentially offering novel approaches to enhance the efficacy of conventional chemotherapy and radiation treatment through targeted sensitization.