肝细胞癌 (HCC) 源自慢性炎症，肝星状细胞 (HSC) 的激活通过塑造促肿瘤微环境而发挥作用。这一过程的关键是 p62，其失活会导致肝癌发生增强。在这里，我们发现 p62 通过促进 HSC 中三联基序蛋白 32 (TRIM32) 的 STING 泛素化来激活干扰素 (IFN) 级联。 p62 是 BRCA1 基因 1 (NBR1) 和 STING 的结合邻居，通过取代 NBR1 触发 IFN 级联，而 NBR1 通常会阻止 TRIM32 与 STING 的相互作用及其随后的激活。此外，NBR1 还通过促进 STING 运输到内体-溶酶体区室进行不依赖自噬的降解来拮抗 STING。与功能相关的是，NBR1 缺失通过拯救受抑制的 STING-IFN 通路，完全恢复 p62 缺陷型 HSC 的促肿瘤功能，从而增强 CD8 T 细胞介导的抗肿瘤反应。因此，NBR1 通过促进 STING/IFN 通路，成为 HSC 中 p62 缺陷的综合脆弱性，从而增强抗肿瘤 CD8 T 细胞反应，抑制 HCC 进展。版权所有 © 2024 Elsevier Inc. 保留所有权利。

Hepatocellular carcinoma (HCC) emerges from chronic inflammation, to which activation of hepatic stellate cells (HSCs) contributes by shaping a pro-tumorigenic microenvironment. Key to this process is p62, whose inactivation leads to enhanced hepatocarcinogenesis. Here, we show that p62 activates the interferon (IFN) cascade by promoting STING ubiquitination by tripartite motif protein 32 (TRIM32) in HSCs. p62, binding neighbor of BRCA1 gene 1 (NBR1) and STING, triggers the IFN cascade by displacing NBR1, which normally prevents the interaction of TRIM32 with STING and its subsequent activation. Furthermore, NBR1 also antagonizes STING by promoting its trafficking to the endosome-lysosomal compartment for degradation independent of autophagy. Of functional relevance, NBR1 deletion completely reverts the tumor-promoting function of p62-deficient HSCs by rescuing the inhibited STING-IFN pathway, thus enhancing anti-tumor responses mediated by CD8+ T cells. Therefore, NBR1 emerges as a synthetic vulnerability of p62 deficiency in HSCs by promoting the STING/IFN pathway, which boosts anti-tumor CD8+ T cell responses to restrain HCC progression.Copyright © 2024 Elsevier Inc. All rights reserved.