How cancer cells escape immune surveillance and resist immune checkpoint blockade (ICB) remains to be fully elucidated. By screening candidate genes frequently gained in cancer, we identified expression of ubiquitin-like modifier activating enzyme 1 (UBA1) as being the most negatively correlated with signatures related to effector CD8+ T-cells. High UBA1 expression was strongly predictive of treatment resistance and poor survival in ICB cohorts. Functional studies revealed that UBA1 mediated immune escape to promote tumor growth. Immune profiling further showed that Uba1 overexpression or depletion markedly decreased or increased functional intratumoral CD8+ T-cells, respectively. Importantly, a selective UBA1 inhibitor, TAK-243, significantly synergized with ICB in multiple syngeneic models. Mechanistically, depletion or inactivation of the UBA1-STUB1 axis stabilized a key interferon pathway component (JAK1), enhanced IFN-signaling, and elevated key immune modulators, including CXCL9, CXCL10, and MHC class I. Our study warrants clinical evaluation of the combination of UBA1 inhibitors and ICB.

中文翻译：

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UBA1-STUB1 轴介导癌症免疫逃逸和对检查点阻断的抵抗


癌细胞如何逃避免疫监视并抵抗免疫检查点阻断 （ICB） 仍有待完全阐明。通过筛选癌症中经常获得的候选基因，我们确定泛素样修饰激活酶 1 （UBA1） 的表达与效应 CD8+ T 细胞相关的特征呈负相关。在 ICB 队列中，高 UBA1 表达强烈预测治疗耐药和不良生存率。功能研究表明，UBA1 介导免疫逃逸以促进肿瘤生长。免疫分析进一步显示，Uba1 过表达或耗竭分别显着减少或增加功能性瘤内 CD8+ T 细胞。重要的是，选择性 UBA1 抑制剂 TAK-243 在多个同基因模型中与 ICB 显著协同作用。从机制上讲，UBA1-STUB1 轴的耗竭或失活稳定了关键干扰素通路成分 （JAK1），增强了 IFN 信号传导，并提高了关键免疫调节剂，包括 CXCL9、CXCL10 和 MHC I 类。我们的研究需要对 UBA1 抑制剂和 ICB 的组合进行临床评估。