Targeting USP1 Potentiates Radiation‐Induced Type I IFN‐Dependent Antitumor Immunity by Enhancing Oligo‐Ubiquitinated SAR1A‐Mediated STING Trafficking and Activation
Abstract The magnitude of Type I interferon (IFN) mediated innate immune response within the tumor microenvironment (TME) critically influences the effectiveness of radiotherapy. Unfortunately, due to a myriad of resistance mechanisms, the double‐stranded DNA (dsDNA) signals produced by tumor cells...
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Wiley
2025-04-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202412687 |
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| author | Weilin Zhou Yuxuan Zhao Wenjing Qin Weijian Wu Chenyang Liao Yiqiu Zhang Xingli Yang Xue Chen Youqiao Wang Yushan Kang Jiaxin Wu Jiaojiao Zhao Junmin Quan Xuecen Wang Xianzhang Bu Xin Yue |
| author_facet | Weilin Zhou Yuxuan Zhao Wenjing Qin Weijian Wu Chenyang Liao Yiqiu Zhang Xingli Yang Xue Chen Youqiao Wang Yushan Kang Jiaxin Wu Jiaojiao Zhao Junmin Quan Xuecen Wang Xianzhang Bu Xin Yue |
| author_sort | Weilin Zhou |
| collection | DOAJ |
| description | Abstract The magnitude of Type I interferon (IFN) mediated innate immune response within the tumor microenvironment (TME) critically influences the effectiveness of radiotherapy. Unfortunately, due to a myriad of resistance mechanisms, the double‐stranded DNA (dsDNA) signals produced by tumor cells postradiotherapy often induce a diminished response from immune cells. Through chemical screening targeting deubiquitinating enzymes, we identified USP1 (Ubiquitin Specific Peptidase 1) inhibitor as an enhancer of post‐radiotherapy dsDNA responses. Mechanistically, within the context of immune‐stimulatory cells in TME, USP1 serves as a suppressor in the stress‐mediated stages of the cGAS (Cyclic GMP‐AMP synthase) ‐STING (Stimulator of interferon genes protein) signaling pathway, specifically affecting the trafficking of STING from endoplasmic reticulum to Golgi apparatus. It is elucidated that SAR1A (Secretion associated Ras related GTPase 1A) requires K27‐linked oligo‐ubiquitination to assemble the STING‐COP‐II (Coat protein II) transport complex for STING trafficking. USP1 counteracts this activation by removing SAR1A ubiquitination, thereby blocking STING trafficking and activation. Consequently, pharmacological USP1 inhibition using ML323 sustains SAR1A ubiquitination and COP‐II complex formation, significantly enhancing STING trafficking and subsequent Type I IFN production. This intervention substantially amplifies radiotherapy‐induced immune activation in the TME, providing a strategic approach to overcome therapeutic resistance and synergize radiotherapy with immunotherapies. |
| format | Article |
| id | doaj-art-3ec5addfa24e4febad8f5ae106a8b3e4 |
| institution | DOAJ |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-3ec5addfa24e4febad8f5ae106a8b3e42025-08-20T03:18:05ZengWileyAdvanced Science2198-38442025-04-011215n/an/a10.1002/advs.202412687Targeting USP1 Potentiates Radiation‐Induced Type I IFN‐Dependent Antitumor Immunity by Enhancing Oligo‐Ubiquitinated SAR1A‐Mediated STING Trafficking and ActivationWeilin Zhou0Yuxuan Zhao1Wenjing Qin2Weijian Wu3Chenyang Liao4Yiqiu Zhang5Xingli Yang6Xue Chen7Youqiao Wang8Yushan Kang9Jiaxin Wu10Jiaojiao Zhao11Junmin Quan12Xuecen Wang13Xianzhang Bu14Xin Yue15School of Pharmaceutical Sciences Sun Yat‐Sen University Guangzhou Guangdong 510006 ChinaSchool of Pharmaceutical Sciences Sun Yat‐Sen University Guangzhou Guangdong 510006 ChinaThe First Affiliated Hospital Jinan University Guangzhou Guangdong 510630 ChinaSchool of Pharmaceutical Sciences Sun Yat‐Sen University Guangzhou Guangdong 510006 ChinaSchool of Pharmaceutical Sciences Sun Yat‐Sen University Guangzhou Guangdong 510006 ChinaSchool of Pharmaceutical Sciences Sun Yat‐Sen University Guangzhou Guangdong 510006 ChinaDepartment of Radiation Oncology The First Affiliated Hospital Sun Yat‐sen University Guangzhou Guangdong 510080 ChinaState Key Laboratory of Oncology in South China Guangdong Provincial Clinical Research Center for Cancer Sun Yat‐sen University Cancer Center Guangzhou Guangdong 510257 ChinaSchool of Pharmaceutical Sciences Sun Yat‐Sen University Guangzhou Guangdong 510006 ChinaSchool of Pharmaceutical Sciences Sun Yat‐Sen University Guangzhou Guangdong 510006 ChinaState Key Laboratory of Oncology in South China Guangdong Provincial Clinical Research Center for Cancer Sun Yat‐sen University Cancer Center Guangzhou Guangdong 510257 ChinaSchool of Pharmaceutical Sciences Sun Yat‐Sen University Guangzhou Guangdong 510006 ChinaLaboratory of Chemical Oncogenomics Guangdong Provincial Key Laboratory of Chemical Genomics Peking University Shenzhen Graduate School Shenzhen Guangdong 518072 ChinaDepartment of Radiation Oncology The First Affiliated Hospital Sun Yat‐sen University Guangzhou Guangdong 510080 ChinaSchool of Pharmaceutical Sciences Sun Yat‐Sen University Guangzhou Guangdong 510006 ChinaThe First Affiliated Hospital Jinan University Guangzhou Guangdong 510630 ChinaAbstract The magnitude of Type I interferon (IFN) mediated innate immune response within the tumor microenvironment (TME) critically influences the effectiveness of radiotherapy. Unfortunately, due to a myriad of resistance mechanisms, the double‐stranded DNA (dsDNA) signals produced by tumor cells postradiotherapy often induce a diminished response from immune cells. Through chemical screening targeting deubiquitinating enzymes, we identified USP1 (Ubiquitin Specific Peptidase 1) inhibitor as an enhancer of post‐radiotherapy dsDNA responses. Mechanistically, within the context of immune‐stimulatory cells in TME, USP1 serves as a suppressor in the stress‐mediated stages of the cGAS (Cyclic GMP‐AMP synthase) ‐STING (Stimulator of interferon genes protein) signaling pathway, specifically affecting the trafficking of STING from endoplasmic reticulum to Golgi apparatus. It is elucidated that SAR1A (Secretion associated Ras related GTPase 1A) requires K27‐linked oligo‐ubiquitination to assemble the STING‐COP‐II (Coat protein II) transport complex for STING trafficking. USP1 counteracts this activation by removing SAR1A ubiquitination, thereby blocking STING trafficking and activation. Consequently, pharmacological USP1 inhibition using ML323 sustains SAR1A ubiquitination and COP‐II complex formation, significantly enhancing STING trafficking and subsequent Type I IFN production. This intervention substantially amplifies radiotherapy‐induced immune activation in the TME, providing a strategic approach to overcome therapeutic resistance and synergize radiotherapy with immunotherapies.https://doi.org/10.1002/advs.202412687K27‐Ubn‐SAR1AradiotherapySTING trafficking and activationtargeting USP1Type I IFNs |
| spellingShingle | Weilin Zhou Yuxuan Zhao Wenjing Qin Weijian Wu Chenyang Liao Yiqiu Zhang Xingli Yang Xue Chen Youqiao Wang Yushan Kang Jiaxin Wu Jiaojiao Zhao Junmin Quan Xuecen Wang Xianzhang Bu Xin Yue Targeting USP1 Potentiates Radiation‐Induced Type I IFN‐Dependent Antitumor Immunity by Enhancing Oligo‐Ubiquitinated SAR1A‐Mediated STING Trafficking and Activation Advanced Science K27‐Ubn‐SAR1A radiotherapy STING trafficking and activation targeting USP1 Type I IFNs |
| title | Targeting USP1 Potentiates Radiation‐Induced Type I IFN‐Dependent Antitumor Immunity by Enhancing Oligo‐Ubiquitinated SAR1A‐Mediated STING Trafficking and Activation |
| title_full | Targeting USP1 Potentiates Radiation‐Induced Type I IFN‐Dependent Antitumor Immunity by Enhancing Oligo‐Ubiquitinated SAR1A‐Mediated STING Trafficking and Activation |
| title_fullStr | Targeting USP1 Potentiates Radiation‐Induced Type I IFN‐Dependent Antitumor Immunity by Enhancing Oligo‐Ubiquitinated SAR1A‐Mediated STING Trafficking and Activation |
| title_full_unstemmed | Targeting USP1 Potentiates Radiation‐Induced Type I IFN‐Dependent Antitumor Immunity by Enhancing Oligo‐Ubiquitinated SAR1A‐Mediated STING Trafficking and Activation |
| title_short | Targeting USP1 Potentiates Radiation‐Induced Type I IFN‐Dependent Antitumor Immunity by Enhancing Oligo‐Ubiquitinated SAR1A‐Mediated STING Trafficking and Activation |
| title_sort | targeting usp1 potentiates radiation induced type i ifn dependent antitumor immunity by enhancing oligo ubiquitinated sar1a mediated sting trafficking and activation |
| topic | K27‐Ubn‐SAR1A radiotherapy STING trafficking and activation targeting USP1 Type I IFNs |
| url | https://doi.org/10.1002/advs.202412687 |
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