免疫检查点抑制剂（ICI）在治疗肝细胞癌（HCC）中的功效仍然有限，这突出表明需要进一步研究其潜在机制。越来越多的证据表明，肿瘤微环境（TME）内的肿瘤相关巨噬细胞（TAM）与免疫逃避和治疗抵抗有关。本研究旨在探讨 TAM 在 HCC TME 中的贡献。我们的研究结果揭示了 CX3C 基序趋化因子受体 1 (CX3CR1) 阳性 TAM 在通过白细胞介素 27 (IL-27) 分泌诱导 T 细胞耗竭方面发挥着关键作用，为了解抗 PD-1 疗效欠佳的机制提供了宝贵的见解HCC 的治疗。此外，我们发现免疫攻击肿瘤细胞释放的前列腺素 E2 (PGE2) 是 CX3CR1 TAM 表型转变的关键调节因子。为了增强当前抗 PD-1 疗法的治疗反应，我们提出了一种创新的治疗策略，除了抗 PD-1 疗法外，还结合了靶向 CX3CR1 TAM。总之，我们的研究有助于理解 TAM 在癌症免疫治疗中的作用，并强调了对 HCC 治疗的潜在临床意义。靶向 CX3CR1 TAM 与抗 PD-1 疗法的结合有望增强 HCC 患者免疫治疗干预的疗效。

The efficacy of immune checkpoint inhibitors (ICI) in the treatment of hepatocellular carcinoma (HCC) remains limited, highlighting the need for further investigation into the underlying mechanisms. Accumulating evidence indicates that tumor-associated macrophages (TAMs) within the tumor microenvironment (TME) are implicated in immune evasion and treatment resistance. This study aimed to explore the contribution of TAMs in the HCC TME. Our findings reveal 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. Moreover, we identified prostaglandin E2 (PGE2), released by immune-attacked tumor cells, as a key regulator of CX3CR1+ TAM phenotype transition. To augment the therapeutic response to current anti-PD-1 therapy, we propose an innovative treatment strategy that incorporates targeting CX3CR1+ TAMs in addition to anti-PD-1 therapy. In conclusion, our study contributes to the understanding of TAMs' role in cancer immunotherapy and highlights potential clinical implications for HCC treatment. The combination of targeting CX3CR1+ TAMs with anti-PD-1 therapy holds promise for enhancing the efficacy of immunotherapeutic interventions in HCC patients.