CDC20‐Mediated Selective Autophagy Degradation of PBRM1 Affects Immunotherapy for Renal Cell Carcinoma
Abstract Polybromo 1 (PBRM1) inactivating mutations are associated with clinical benefit from immune checkpoint inhibitor treatments in clear cell renal cell carcinoma (ccRCC). However, whether targeting PBRM1 has the potential to enhance immunotherapy efficacy in patients with wild‐type PBRM1 and t...
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Wiley
2025-02-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202412967 |
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| author | Yizeng Fan Weichao Dan Taotao Que Yi Wei Bo Liu Zixi Wang Yulin Zhang Yuzhao Wang Tianjie Liu Yanxin Zhuang Mengxing Li Chendong Guo Jin Zeng Bohan Ma Lei Li |
| author_facet | Yizeng Fan Weichao Dan Taotao Que Yi Wei Bo Liu Zixi Wang Yulin Zhang Yuzhao Wang Tianjie Liu Yanxin Zhuang Mengxing Li Chendong Guo Jin Zeng Bohan Ma Lei Li |
| author_sort | Yizeng Fan |
| collection | DOAJ |
| description | Abstract Polybromo 1 (PBRM1) inactivating mutations are associated with clinical benefit from immune checkpoint inhibitor treatments in clear cell renal cell carcinoma (ccRCC). However, whether targeting PBRM1 has the potential to enhance immunotherapy efficacy in patients with wild‐type PBRM1 and the upstream pathways that regulate PBRM1 protein stability remain unclear. Here, it is demonstrated that PBRM1 knockdown induced M1 macrophage polarization and infiltration, which enhanced the efficacy of anti‐PD‐1 immunotherapy in RCC. Meanwhile, CDC20 catalyzes K27 ubiquitination of PBRM1 and promotes its degradation via p62‐mediated selective autophagy. A bicyclic peptide (PB1‐p62) is designed and constructed to target PBRM1 and p62, thereby promoting the degradation of PBRM1. As a result, the efficacy of anti‐PD‐1 immunotherapy is enhanced, leading to improved overall survival rates in syngeneic mouse tumor models. Overall, this finding suggest the clinical application of PB1‐p62 and provide a novel approach for enhancing the effectiveness of immunotherapy in RCC patients with wild‐type PBRM1. |
| format | Article |
| id | doaj-art-a5984a8423bd4ffb9466409d3b4fdf34 |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-a5984a8423bd4ffb9466409d3b4fdf342025-02-04T13:14:54ZengWileyAdvanced Science2198-38442025-02-01125n/an/a10.1002/advs.202412967CDC20‐Mediated Selective Autophagy Degradation of PBRM1 Affects Immunotherapy for Renal Cell CarcinomaYizeng Fan0Weichao Dan1Taotao Que2Yi Wei3Bo Liu4Zixi Wang5Yulin Zhang6Yuzhao Wang7Tianjie Liu8Yanxin Zhuang9Mengxing Li10Chendong Guo11Jin Zeng12Bohan Ma13Lei Li14Department of Urology The First Affiliated Hospital of Xi'an Jiaotong University Xi'an Shaanxi 710061 P. R. ChinaDepartment of Urology The First Affiliated Hospital of Xi'an Jiaotong University Xi'an Shaanxi 710061 P. R. ChinaDepartment of Urology The First Affiliated Hospital of Xi'an Jiaotong University Xi'an Shaanxi 710061 P. R. ChinaDepartment of Urology The First Affiliated Hospital of Xi'an Jiaotong University Xi'an Shaanxi 710061 P. R. ChinaDepartment of Urology The First Affiliated Hospital of Xi'an Jiaotong University Xi'an Shaanxi 710061 P. R. ChinaDepartment of Urology The First Affiliated Hospital of Xi'an Jiaotong University Xi'an Shaanxi 710061 P. R. ChinaDepartment of Urology The First Affiliated Hospital of Xi'an Jiaotong University Xi'an Shaanxi 710061 P. R. ChinaDepartment of Urology The First Affiliated Hospital of Xi'an Jiaotong University Xi'an Shaanxi 710061 P. R. ChinaDepartment of Urology The First Affiliated Hospital of Xi'an Jiaotong University Xi'an Shaanxi 710061 P. R. ChinaDepartment of Urology The First Affiliated Hospital of Xi'an Jiaotong University Xi'an Shaanxi 710061 P. R. ChinaDepartment of Urology The First Affiliated Hospital of Xi'an Jiaotong University Xi'an Shaanxi 710061 P. R. ChinaDepartment of Urology The First Affiliated Hospital of Xi'an Jiaotong University Xi'an Shaanxi 710061 P. R. ChinaDepartment of Urology The First Affiliated Hospital of Xi'an Jiaotong University Xi'an Shaanxi 710061 P. R. ChinaDepartment of Urology The First Affiliated Hospital of Xi'an Jiaotong University Xi'an Shaanxi 710061 P. R. ChinaDepartment of Urology The First Affiliated Hospital of Xi'an Jiaotong University Xi'an Shaanxi 710061 P. R. ChinaAbstract Polybromo 1 (PBRM1) inactivating mutations are associated with clinical benefit from immune checkpoint inhibitor treatments in clear cell renal cell carcinoma (ccRCC). However, whether targeting PBRM1 has the potential to enhance immunotherapy efficacy in patients with wild‐type PBRM1 and the upstream pathways that regulate PBRM1 protein stability remain unclear. Here, it is demonstrated that PBRM1 knockdown induced M1 macrophage polarization and infiltration, which enhanced the efficacy of anti‐PD‐1 immunotherapy in RCC. Meanwhile, CDC20 catalyzes K27 ubiquitination of PBRM1 and promotes its degradation via p62‐mediated selective autophagy. A bicyclic peptide (PB1‐p62) is designed and constructed to target PBRM1 and p62, thereby promoting the degradation of PBRM1. As a result, the efficacy of anti‐PD‐1 immunotherapy is enhanced, leading to improved overall survival rates in syngeneic mouse tumor models. Overall, this finding suggest the clinical application of PB1‐p62 and provide a novel approach for enhancing the effectiveness of immunotherapy in RCC patients with wild‐type PBRM1.https://doi.org/10.1002/advs.202412967CDC20Immunotherapyp62PBRM1RCC |
| spellingShingle | Yizeng Fan Weichao Dan Taotao Que Yi Wei Bo Liu Zixi Wang Yulin Zhang Yuzhao Wang Tianjie Liu Yanxin Zhuang Mengxing Li Chendong Guo Jin Zeng Bohan Ma Lei Li CDC20‐Mediated Selective Autophagy Degradation of PBRM1 Affects Immunotherapy for Renal Cell Carcinoma Advanced Science CDC20 Immunotherapy p62 PBRM1 RCC |
| title | CDC20‐Mediated Selective Autophagy Degradation of PBRM1 Affects Immunotherapy for Renal Cell Carcinoma |
| title_full | CDC20‐Mediated Selective Autophagy Degradation of PBRM1 Affects Immunotherapy for Renal Cell Carcinoma |
| title_fullStr | CDC20‐Mediated Selective Autophagy Degradation of PBRM1 Affects Immunotherapy for Renal Cell Carcinoma |
| title_full_unstemmed | CDC20‐Mediated Selective Autophagy Degradation of PBRM1 Affects Immunotherapy for Renal Cell Carcinoma |
| title_short | CDC20‐Mediated Selective Autophagy Degradation of PBRM1 Affects Immunotherapy for Renal Cell Carcinoma |
| title_sort | cdc20 mediated selective autophagy degradation of pbrm1 affects immunotherapy for renal cell carcinoma |
| topic | CDC20 Immunotherapy p62 PBRM1 RCC |
| url | https://doi.org/10.1002/advs.202412967 |
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