Blocking CX3CR1+ Tumor-associated Macrophages Synergize with anti-PD-1 Therapy in Hepatocellular Carcinoma

The efficacy of immune checkpoint inhibitors (ICI) in hepatocellular carcinoma (HCC) treatment remains limited, warranting further investigation into the underlying mechanisms. Accumulating evidence indicates that myeloid cells within the tumor microenvironment (TME) play a role in immune evasion and treatment resistance. In this study, we aimed to explore the contribution of tumor-associated macrophages (TAMs) in the HCC TME. Our findings unveil the critical involvement of CX3C motif chemokine receptor 1 (CX3CR1)-positive TAMs in inducing T cell exhaustion through interleukin-27 (IL-27) secretion, providing valuable insights into the mechanisms underlying the suboptimal efficacy of anti-PD-1 therapy in HCC. Additionally, we identified prostaglandin E2 (PGE2) released by immune-attacked tumor cells as a key driver of CX3CR1+ TAM recruitment. To enhance the therapeutic response to current anti-PD-1 therapy, we propose a novel treatment strategy that combines targeted depletion of CX3CR1+ TAMs with anti-PD-1 therapy. Overall, our study contributes to the understanding of TAMs' role in cancer immunotherapy and presents potential clinical implications for HCC treatment. By targeting CX3CR1+ TAMs in conjunction with anti-PD-1 therapy, we have the potential to enhance the effectiveness of immunotherapeutic interventions in HCC patients.