该研究表明， 活化的 ATF6α 是一种肝肿瘤驱动因子，可限制免疫监视，其可作为免疫检查点阻断 （ICB） 疗法响应的潜在分层标志物，也是肝细胞癌的治疗新 靶点。 撰文丨王聪 编辑丨王多鱼 排版丨水成文 肝细胞癌 （HCC）， 主要源自慢性肝炎中恶性转化的肝细胞，其 占原发性肝癌的 80% - 85%。尽管免疫疗法的进步提高了肝细胞癌患者的生存率，但复杂的 遗传、代谢和炎症相互作用仍是有效治疗的障碍。 肝细胞癌浸润淋巴细胞表达耗竭标志物 （例如 PD-1、CTLA-4） ，导致预后不良。免疫检查点阻断 （阿特珠单抗） 和血管内皮生长因子 （VEGF） 阻断 （贝 伐珠单抗） 以改善 T 细胞介导的肿瘤监视是不可切除肝细胞癌的标准治疗方法。然而，肝细胞癌中的代谢重编程 （包括葡萄糖剥夺和肿瘤内缺氧环境） ，会降 低抗肿瘤治疗效果并增强恶性程度。因此，需要新的策略来克服与代谢相关的肿瘤逃逸和免疫抑制。 2026 年 2 月 4 日， 德国癌症研究中心 Li Xin 作为第一作者，在国际顶尖学术期刊 Nature 上发表了题为： Activated ATF6α is a hepatic tumour driver ...

Core Viewpoint - The study reveals that macrophage PD-1 plays a critical role in the intersection of immune checkpoint blockade, energy expenditure, and metabolic dysfunction, providing a new theoretical basis for combating metabolic diseases induced by immune checkpoint inhibitors and high-fat diets [7]. Group 1: Research Findings - The research indicates that anti-PD-1 antibodies target macrophage PD-1, reducing energy expenditure without affecting food intake, thereby increasing susceptibility to obesity and systemic metabolic disorders induced by high-fat diets [4]. - The mechanism involves lipopolysaccharide (LPS) activating Unc-51-like autophagy activating kinase-1 (ULK1) in an mTOR-dependent manner, which phosphorylates PD-1 at the Thr250 site, preventing its ubiquitination and degradation by FBXO38 [4][8]. - Phosphorylated PD-1 interacts with IRE1α, inhibiting its phosphorylation and thereby suppressing inflammation driven by endoplasmic reticulum stress [4][8]. Group 2: Implications - The findings suggest that targeting IRE1α-XBP1 may offer a potential strategy to counteract metabolic dysfunction induced by immune checkpoint inhibitors [8]. - The study's insights into the dual role of macrophage PD-1 could lead to new therapeutic approaches for managing metabolic disorders associated with cancer treatments [7].