Simple SummaryIn this study, we investigated the potential of TLR4 to improve the treatment of hepatocellular carcinoma (HCC). HCC is a serious health concern worldwide, and finding new ways to combat it is crucial. Our study focused on understanding how TLR4 can enhance the effectiveness of immunotherapy, a treatment approach that harnesses the body’s immune system to fight cancer cells. We demonstrated that targeting TLR4 can stimulate the immune response against HCC cells, leading to their destruction. This exciting finding suggests that TLR4 could serve as a valuable target for developing new therapies for HCC. The implications of this study extend beyond the realm of medical research. If successful, these new strategies could offer renewed hope to HCC patients and potentially improve the overall survival rates. Furthermore, the insights gained from our study may pave the way for similar approaches in treating other types of cancer. In summary, our research highlights the significant role of TLR4 in enhancing immunotherapy for HCC. This knowledge brings us one step closer to developing more effective treatments and improving the lives of cancer patients.AbstractHepatocellular carcinoma (HCC) is the most common type of primary liver cancer and is a leading cause of cancer-related death worldwide. Immunotherapy has emerged as the mainstay treatment option for unresectable HCC. Toll-like receptor 4 (TLR4) plays a crucial role in the innate immune response by recognizing and responding primarily to bacterial lipopolysaccharides. In addition to its role in the innate immune system, TLR4 has also been implicated in adaptive immunity, including specific anti-tumor immune responses. In particular, the TLR4 signaling pathway seems to be involved in the regulation of several cancer hallmarks, such as the continuous activation of cellular pathways that promote cell division and growth, the inhibition of programmed cell death, the promotion of several invasion and metastatic mechanisms, epithelial-to-mesenchymal transition, angiogenesis, drug resistance, and epigenetic modifications. Emerging evidence further suggests that TLR4 signaling holds promise as a potential immunotherapeutic target in HCC. The aim of this review was to explore the multilayer aspects of the TLR4 signaling pathway, regarding its role in liver diseases and HCC, as well as its potential utilization as an immunotherapy target for HCC.