免疫检查点阻断（ICB）治疗在肝细胞癌（HCC）中的效果有限。本研究探讨了利用肿瘤代谢转换增强HCC对免疫疗法的敏感性的可能性。评估了HCC非肿瘤和肿瘤组织中一碳（1C）代谢水平和磷酸丝氨酸磷酸酶（PSPH）的表达，PSPH是1C途径的上游酶。通过体外和体内实验研究了调节单核/巨噬细胞和CD8+ T淋巴细胞浸润的PSPH的作用机制。HCC肿瘤组织中PSPH明显上调，其水平与疾病进展呈正相关。PSPH敲低抑制了免疫竞争小鼠的肿瘤生长，但对单核/巨噬细胞或T淋巴细胞缺陷小鼠的肿瘤生长没有影响，说明PSPH的促肿瘤作用依赖于两种免疫成分。机制上，PSPH通过诱导C-C基序趋化因子2（CCL2）的产生促进单核/巨噬细胞浸润，同时通过抑制肿瘤坏死因子α（TNF-α）条件下C-X-C基序趋化因子10（CXCL10）的产生减少CD8+ T淋巴细胞的招募。谷胱甘肽和S-腺苷甲硫氨酸部分参与了CCL2和CXCL10的调控。Cancer细胞的shPSPH（短发夹RNA）转染增强了肿瘤对抗程序性细胞死亡蛋白1（PD-1）治疗的敏感性，而且metformin可以抑制癌细胞中的PSPH表达并模拟shPSPH的作用，增强肿瘤对抗PD-1治疗的疗效。通过将免疫平衡向肿瘤友好组成倾斜，PSPH可能既可作为ICB治疗中患者分层的标志物，也可作为治疗人类HCC的有吸引力的治疗靶点。 ©作者（或其雇主）2023年。CC BY-NC允许再利用。不得进行商业再利用。由BMJ发布。

Effects of immune checkpoint blockade (ICB) treatment in hepatocellular carcinoma (HCC) are limited. The current study explored the possibility of exploiting tumor metabolic switches to enhance HCC sensitivity to immune therapies.Levels of one-carbon (1C) metabolism and the expression of phosphoserine phosphatase (PSPH), an upstream enzyme of 1C pathway, were evaluated in paired non-tumor and tumor tissues from HCC. Underlying mechanisms mediating the role of PSPH in regulating the infiltration of monocytes/macrophages and CD8+ T lymphocytes were studied through both in vitro and in vivo experiments.PSPH was significantly upregulated in tumor tissues of HCC and its levels were positively correlated with disease progression. PSPH knockdown inhibited tumor growth in immunocompetent mice, but not in those with macrophage or T lymphocyte deficiencies, indicating the pro-tumor effects of PSPH were dependent on both immune components. Mechanistically, PSPH facilitated monocytes/macrophages infiltration by inducing the production of C-C motif chemokine 2 (CCL2), while at the same time reduced CD8+ T lymphocytes recruitment through inhibiting the production of C-X-C Motif Chemokine 10 (CXCL10) in tumor necrosis factor alpha (TNF-α)-conditioned cancer cells. Glutathione and S-adenosyl-methionine were partially involved in regulating the production of CCL2 and CXCL10, respectively. shPSPH (short hairpin RNA) transfection of cancer cells enhanced tumor sensitivity to anti-programmed cell death protein 1 (PD-1) therapy in vivo, and interestingly, metformin could inhibit PSPH expression in cancer cells and mimic the effects of shPSPH in sensitizing tumors to anti-PD-1 treatment.By tilting the immune balance towards a tumor-friendly composition, PSPH might be useful both as a marker in stratifying patients for ICB therapy, and as an attractive therapeutic target in the treatment of human HCC.© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.