肝癌的代谢特征给免疫细胞功能和癌症免疫治疗带来了相当大的障碍。然而，肿瘤微环境中的代谢重编程如何损害抗肿瘤免疫反应仍不清楚。采用人类样本和多个小鼠模型来评估GPR109A与肝癌进展之间的相关性。采用 GPR109A 敲除小鼠、免疫细胞耗竭和原代细胞共培养模型来确定 GPR109A 对肿瘤微环境的调节，并确定肿瘤内 GPR109A 髓样细胞形成的潜在机制。免疫抑制性 GPR109A 骨髓细胞浸润，导致逃避免疫监视。阻断 GPR109A 会降低 G-MDSC 和 M2 样 TAM 丰度，从而触发 CD8 T 细胞的抗肿瘤反应，并进一步提高肝癌的免疫治疗效果。从机制上讲，肿瘤细胞和肿瘤浸润的骨髓细胞通过转运蛋白SLC1A5竞争谷氨酰胺的摄取来控制抗肿瘤免疫，从而破坏内质网（ER）稳态并诱导骨髓细胞的未折叠蛋白反应，通过IRE1α/XBP1途径促进GPR109A表达。限制肝癌细胞中谷氨酰胺的摄取，以及阻断 IRE1α/XBP1 信号传导或补充谷氨酰胺，可以消除 GPR109A 骨髓细胞的免疫抑制作用并减缓肿瘤进展。我们的研究结果确定了肝癌细胞和肝癌细胞之间的免疫代谢串扰。骨髓细胞通过谷氨酰胺代谢/内质网应激/GPR109A 轴促进肿瘤进展，表明 GPR109A 可以用作免疫代谢检查点和癌症治疗的推定靶点。© 作者（或其雇主）2024 年。无商业用途重复使用。请参阅权利和权限。英国医学杂志出版。

The metabolic characteristics of liver cancer drive considerable hurdles to immune cells function and cancer immunotherapy. However, how metabolic reprograming in the tumour microenvironment impairs the antitumour immune response remains unclear.Human samples and multiple murine models were employed to evaluate the correlation between GPR109A and liver cancer progression. GPR109A knockout mice, immune cells depletion and primary cell coculture models were used to determine the regulation of GPR109A on tumour microenvironment and identify the underlying mechanism responsible for the formation of intratumour GPR109A+myeloid cells.We demonstrate that glutamine shortage in liver cancer tumour microenvironment drives an immunosuppressive GPR109A+myeloid cells infiltration, leading to the evasion of immune surveillance. Blockade of GPR109A decreases G-MDSCs and M2-like TAMs abundance to trigger the antitumour responses of CD8+ T cells and further improves the immunotherapy efficacy against liver cancer. Mechanistically, tumour cells and tumour-infiltrated myeloid cells compete for glutamine uptake via the transporter SLC1A5 to control antitumour immunity, which disrupts the endoplasmic reticulum (ER) homoeostasis and induces unfolded protein response of myeloid cells to promote GPR109A expression through IRE1α/XBP1 pathway. The restriction of glutamine uptake in liver cancer cells, as well as the blockade of IRE1α/XBP1 signalling or glutamine supplementation, can eliminate the immunosuppressive effects of GPR109A+ myeloid cells and slow down tumour progression.Our findings identify the immunometabolic crosstalk between liver cancer cells and myeloid cells facilitates tumour progression via a glutamine metabolism/ER stress/GPR109A axis, suggesting that GPR109A can be exploited as an immunometabolic checkpoint and putative target for cancer treatment.© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.