PO.CL08.01 · 临床研究
USP3稳定STING以增强NSCLC的放射敏感性及抗肿瘤免疫
USP3 stabilizes STING to enhance radiosensitivity and antitumor immunity of NSCLC
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摘要 Abstract
中文摘要
目的：尽管放疗（RT）是非小细胞肺癌（NSCLC）的主要治疗手段，放射抵抗仍是重大挑战，并与失调的肿瘤免疫微环境（TIME）密切相关。免疫放疗通过促进抗肿瘤免疫应答及改变TIME展现出改善的治疗活性。近期研究将STING激活定位为这一免疫重编程的强效催化剂。因此，识别能够增强STING介导免疫激活的上游调节因子，对于制定克服NSCLC放射抵抗的策略至关重要。
方法：使用公共数据集及机构测序数据对泛素特异性蛋白酶3（USP3）的表达模式、免疫浸润特征及通路富集进行分析。通过TCGA数据集评估预后价值，并在105例NSCLC患者的临床队列（天津医科大学肿瘤医院，2013-2015年）中进行验证。随后，我们通过免疫共沉淀及免疫荧光研究USP3与STING之间的相互作用，以及USP3对RT诱导的STING/I型干扰素（IFN-Is）信号的影响。最后，我们评估USP3对RT诱导的肿瘤T细胞浸润以及对RT和放射免疫治疗敏感性的影响。
结果：与正常组织相比，USP3表达在NSCLC标本中显著下调。高USP3表达在公共数据集及我们的独立临床队列中均与总生存期延长相关。功能上，USP3过表达增强NSCLC细胞的放射敏感性并诱导促炎表型。机制上，USP3与STING发生物理相互作用，去除K48连接的多聚泛素链，从而阻止STING的蛋白酶体降解。这一稳定作用放大了cGAS-STING信号及下游IFN-Is的产生。在体内，USP3过表达重塑了照射后的肿瘤免疫微环境，表现为效应性CD8+ T细胞浸润增加及全身抗肿瘤免疫增强。
结论：USP3去泛素化STING并阻断其蛋白酶体降解，从而稳定STING蛋白，增强cGAS-STING轴及I型干扰素信号。这些结果突显USP3是一个有前景的预后生物标志物，以及克服放射抵抗、改善基于放疗治疗策略的潜在治疗靶点。
查看英文原文 English abstract
Purpose: Although radiotherapy (RT) is a predominant treatment for non-small cell lung cancer (NSCLC), radioresistance remains a major challenge and is strongly linked to dysregulated tumor immune microenvironments (TIME). Immunoradiotherapy has shown improved therapeutic activity by promoting antitumor immune responses and modifying the TIME. Recent studies positions STING activation as a potent catalyst of this immune reprogramming. Therefore, identifying upstream regulators capable of enhancing STING-mediated immune activation is critical for developing strategies to overcome radioresistance in NSCLC.
Methods: Ubiquitin-specific protease3 (USP3) expression patterns, immune infiltration profiles, and pathway enrichment analyses were performed using public datasets and institutional sequencing data. Prognostic value was evaluated via TCGA datasets and validated in a clinical cohort of 105 NSCLC patients (Tianjin Medical University Cancer Institute & Hospital, 2013-2015). Subsequently, we investigated the interaction between USP3 and STING and the effects of USP3 on RT-induced STING/type I interferon (IFN-Is) signaling through co-immunoprecipitation and immunofluorescence. Finally, we evaluated the effects of USP3 on RT-induced T cell infiltration in tumor and sensitivity to RT and radioimmunotherapy.
Results : USP3 expression was significantly downregulated in NSCLC specimens compared to normal tissues. High USP3 expression correlated with prolonged overall survival in public datasets and our independent clinical cohort. Functionally, USP3 overexpression enhanced the radiosensitivity of NSCLC cells and induced a pro-inflammatory phenotype. Mechanistically, USP3 physically interacted with STING, removed K48-linked polyubiquitin chains, and thereby prevented proteasomal degradation of STING. This stabilization amplified cGAS-STING signaling and downstream IFN-Is production. In vivo, USP3 overexpression remodeled the post-irradiation tumor immune microenvironment, as evidenced by increased infiltration of effector CD8⁺ T cells and enhanced systemic antitumor immunity.
Conclusion: USP3 deubiquitinates STING and blocks its proteasomal degradation, thereby stabilizing the STING protein, potentiating the cGAS-STING axis and type I interferon signaling. These results highlight USP3 as a promising prognostic biomarker and a potential therapeutic target for overcoming radioresistance and improving radiotherapy-based treatment strategies.
利益披露 Disclosure
Z. Cheng, None..
Z. Cai, None..
Y. Xu, None..
J. yan, None..
Z. Wu, None..
Z. Yuan, None.