Cui Kaisa, Liu Bingxin, Gong Liang, Wan Quan, Tang Hong, Gong Zhicheng, Shen Renhui, Wang Chao, Zhang Qiang, Li Qilin, Zhu Yizhun, Zhang Youming, Lu Xiaojie
Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, 214062, China.
Neuroscience Center, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, 214122, China.
Br J Cancer. 2025 Jul 11. doi: 10.1038/s41416-025-03109-y.
Hyperactive ribosome biogenesis is a hallmark of tumours. Current ribosome-related studies are concentrated on cancer cells. Ribosomes can regulate both tumour and non-cancer cells within the tumour microenvironment, yet the immunomodulatory effects of cellular ribosome biogenesis blockade remain inadequately understood.
We performed ribosome-targeting therapy utilizing CX-5461, an effective and acknowledged selective inhibitor of ribosome biogenesis, in immunocompetent in vivo models and submitted for single-cell RNA sequencing (scRNA-seq). Additional large-scale human scRNA-seq data, in-house clinical samples and assays were used.
Ribosome inhibition elevated lymphoid cell cytotoxic granule secretion and macrophage pro-inflammation reprogramming. We uncovered unique immune cell subpopulations that are sensitive to ribosome biogenesis blockade and are associated with adverse clinical outcomes. Impressively, these cells regress during responsive immune checkpoint blockade (ICB) treatment, revealing that they are essential for immunotherapy efficacy. Moreover, targeting ribosomes induces immune checkpoint expression (such as Lag3) and significantly sensitizes tumours to anti-Lag3 immunotherapy, eliciting potent tumour regression and deeper anti-tumour immune responses.
These findings unravel previously unrecognized roles of cellular ribosome biogenesis in sustaining immunosuppressive non-cancer cells. Our work unveils that ribosome biogenesis blockade could reinstate immunosurveillance and provide novel strategies to enhance the ICB efficacy in patients with poor immunogenicity.
核糖体生物合成亢进是肿瘤的一个标志。目前与核糖体相关的研究主要集中在癌细胞上。核糖体可以调节肿瘤微环境中的肿瘤细胞和非癌细胞，但细胞核糖体生物合成阻断的免疫调节作用仍未得到充分了解。
我们在具有免疫活性的体内模型中使用CX-5461（一种有效且公认的核糖体生物合成选择性抑制剂）进行核糖体靶向治疗，并进行单细胞RNA测序（scRNA-seq）。还使用了额外的大规模人类scRNA-seq数据、内部临床样本和检测方法。
核糖体抑制提高了淋巴细胞细胞毒性颗粒的分泌和巨噬细胞促炎重编程。我们发现了对核糖体生物合成阻断敏感且与不良临床结果相关的独特免疫细胞亚群。令人印象深刻的是，这些细胞在反应性免疫检查点阻断（ICB）治疗期间会消退，这表明它们对免疫治疗疗效至关重要。此外，靶向核糖体可诱导免疫检查点表达（如Lag3），并显著使肿瘤对抗Lag3免疫治疗敏感，引发有效的肿瘤消退和更深层次的抗肿瘤免疫反应。
这些发现揭示了细胞核糖体生物合成在维持免疫抑制性非癌细胞中以前未被认识的作用。我们的工作表明，核糖体生物合成阻断可以恢复免疫监视，并为提高免疫原性较差患者的ICB疗效提供新策略。
