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journal article·2025-10Open access

STK25 Loss Augments Anti‐PD‐1 Therapy Efficacy by Regulating PD‐L1 Stability in Colorectal Cancer

Xiaowen Qiao, Pu Xing, Hao Hao, Jiangbo Chen, Lin Song, Yifan Hou, Xinying Yang, Kai Weng, Jie Chen, Pin Gao, Tongkun Song, Hong Yang, Tianqi Liu, Yumeng Ran, Bo Chen, Wei Zhao, Jiabo Di, Zaozao Wang, Jun Zhang, Xiangqian Su, Beihai Jiang

Advanced Science· Volume 12· Issue 39
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Source abstract

Abstract

Abstract Tumor immune evasion is intricately linked to malignant tumor progression and contributes to the failure of anti‐cancer immunotherapy. Serine/threonine protein kinase 25 (STK25) has been previously implicated in the progression of various neoplastic diseases. However, the function of STK25 in the colorectal cancer (CRC) microenvironment remains unclear. Here, it is demonstrated that STK25 global knockout (STK25 −/− ) mice and STK25‐knockout tumor‐bearing mice exhibited enhanced effectiveness of anti‐PD‐1 immunotherapy, which leads to significant tumor suppression with increased recruitment of CD8 + T cells. Mechanistically, STK25 deficiency increased PD‐L1 protein levels by regulating PD‐L1 K48‐linked ubiquitination in a NEDD4‐dependent manner. Moreover, CRC patients with low STK25 expression are more responsive to immune checkpoint blockade (ICB) therapy compared to those with high STK25 levels. Taken together, the findings reveal a critical role of STK25 for regulating PD‐L1 protein stability in tumor immune evasion, and suggest that targeting STK25 may provide a potential approach to increase sensitivity to the ICB treatment in patients with CRC.
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Research context

OpenAlex topics: Cancer Immunotherapy and Biomarkers · Ferroptosis and cancer prognosis · Immune cells in cancer

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education) Department of Gastrointestinal Surgery IV Peking University Cancer Hospital & Institute Beijing 100142 China

Department of Radiation Oncology Radiation Oncology Key Laboratory of Sichuan Province Sichuan Clinical Research Center for Cancer Sichuan Cancer Hospital &Institute Sichuan Cancer Center Affiliated Cancer Hospital of University of Electronic Science and Technology of China Chengdu Sichuan 610041 China

School of Basic Medical Sciences Peking University Health Science Center Beijing 100191 China

Department of Gastrointestinal Surgery Peking University Cancer Hospital (Inner Mongolia Campus) & Affiliated Cancer Hospital of Inner Mongolia Medical University Hohhot 010010 China

Department of Pathology Peking Union Medical College Hospital Peking Union Medical College and Chinese Academy of Medical Science Beijing 100730 China

Ningxia Clinical Research Institute People's Hospital of Ningxia Hui Autonomous Region Ningxia Medical University Yinchuan 750002 China

Department of Immunology School of Basic Medical Sciences NHC Key Laboratory of Medical Immunology Medicine Innovation Center for Fundamental Research on Major Immunology‐related Diseases Peking University Beijing 100191 China

State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers Department of Gastrointestinal Surgery IV Peking University Cancer Hospital & Institute Beijing 100142 China

Funding

National Natural Science Foundation of China · China Postdoctoral Science Foundation · Natural Science Foundation of Ningxia Province · Natural Science Foundation of Inner Mongolia Autonomous Region

References (62)

Show source-provided references
1. 10.1038/s41575-019-0230-y10.1038/s41575-019-0230-y ↗
2. 10.1016/S0140-6736(19)32319-010.1016/S0140-6736(19)32319-0 ↗
3. 10.1056/NEJMoa201769910.1056/NEJMoa2017699 ↗
4. 10.1001/jamaoncol.2020.091010.1001/jamaoncol.2020.0910 ↗
5. 10.1016/j.it.2018.05.00110.1016/j.it.2018.05.001 ↗
6. 10.1016/j.cell.2017.01.01710.1016/j.cell.2017.01.017 ↗
7. 10.1016/j.ccell.2015.03.00110.1016/j.ccell.2015.03.001 ↗
8. 10.1038/s41577-019-0218-410.1038/s41577-019-0218-4 ↗
9. 10.1038/s41591-019-0522-310.1038/s41591-019-0522-3 ↗
10. 10.1016/j.ccell.2020.02.00610.1016/j.ccell.2020.02.006 ↗
11. 10.1016/j.celrep.2023.11334310.1016/j.celrep.2023.113343 ↗
12. 10.1038/nature1401110.1038/nature14011 ↗
13. 10.1016/j.molmed.2014.10.00910.1016/j.molmed.2014.10.009 ↗
14. 10.1007/s00125-012-2511-710.1007/s00125-012-2511-7 ↗
15. Cansby E. · ASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol. · 2013 · 27 · 3660
16. 10.2337/db15-006010.2337/db15-0060 ↗
17. 10.1523/JNEUROSCI.0523-21.202110.1523/JNEUROSCI.0523-21.2021 ↗
18. Amrutkar M. · ASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol. · 2015 · 29 · 1564
19. 10.1172/jci.insight.16037210.1172/jci.insight.160372 ↗
20. 10.1371/journal.pone.003115210.1371/journal.pone.0031152 ↗
21. 10.1038/s41467-019-09597-w10.1038/s41467-019-09597-w ↗
22. Wu F. · J. Exp. Clin. Cancer Res. CR · 2018 · 37 · 144
23. 10.1002/mc.2340310.1002/mc.23403 ↗
24. 10.1155/2021/648587110.1155/2021/6485871 ↗
25. 10.1186/s12967-022-03536-y10.1186/s12967-022-03536-y ↗
26. 10.1038/s41590-019-0312-610.1038/s41590-019-0312-6 ↗
27. 10.1016/j.apsb.2021.03.02710.1016/j.apsb.2021.03.027 ↗
28. 10.1038/s41467-021-25662-910.1038/s41467-021-25662-9 ↗
29. 10.1038/s41467-023-44466-710.1038/s41467-023-44466-7 ↗
30. 10.3390/cancers1404104210.3390/cancers14041042 ↗
31. 10.1016/j.molcel.2021.03.03710.1016/j.molcel.2021.03.037 ↗
32. 10.1158/0008-5472.CAN-21-236210.1158/0008-5472.CAN-21-2362 ↗
33. 10.1093/annonc/mdy49510.1093/annonc/mdy495 ↗
34. 10.18632/oncotarget.2165410.18632/oncotarget.21654 ↗
35. 10.1016/j.jcmgh.2021.09.01810.1016/j.jcmgh.2021.09.018 ↗
36. 10.1074/jbc.C112.34539710.1074/jbc.C112.345397 ↗
37. 10.1016/j.bbrc.2011.03.03110.1016/j.bbrc.2011.03.031 ↗
38. 10.1038/s41418-023-01219-910.1038/s41418-023-01219-9 ↗
39. 10.1136/jitc-2022-00631110.1136/jitc-2022-006311 ↗
40. 10.1182/bloodadvances.202301201910.1182/bloodadvances.2023012019 ↗
41. 10.1038/nature1552010.1038/nature15520 ↗
42. 10.7150/thno.6944410.7150/thno.69444 ↗
43. 10.1158/1078-0432.CCR-16-321510.1158/1078-0432.CCR-16-3215 ↗
44. 10.1038/nature2364310.1038/nature23643 ↗
45. 10.1016/j.ccell.2018.01.00910.1016/j.ccell.2018.01.009 ↗
46. 10.1038/s41422-018-0124-510.1038/s41422-018-0124-5 ↗
47. 10.1083/jcb.20031006110.1083/jcb.200310061 ↗
48. 10.1200/JCO.22.0227210.1200/JCO.22.02272 ↗
49. 10.1016/S1470-2045(19)30167-610.1016/S1470-2045(19)30167-6 ↗
50. 10.1056/NEJMoa191054910.1056/NEJMoa1910549 ↗
51. 10.1056/NEJMoa160677410.1056/NEJMoa1606774 ↗
52. 10.1016/S0140-6736(15)01281-710.1016/S0140-6736(15)01281-7 ↗
53. 10.1021/ja208518u10.1021/ja208518u ↗
54. 10.3390/cancers1424614610.3390/cancers14246146 ↗
55. 10.1136/jitc-2020-00149610.1136/jitc-2020-001496 ↗
56. 10.1136/jitc-2022-00661910.1136/jitc-2022-006619 ↗
57. 10.1016/j.jcmgh.2018.12.00410.1016/j.jcmgh.2018.12.004 ↗
58. 10.1158/1078-0432.CCR-23-110910.1158/1078-0432.CCR-23-1109 ↗
59. 10.1186/s12916-023-02866-y10.1186/s12916-023-02866-y ↗
60. 10.1038/s42003-022-03309-910.1038/s42003-022-03309-9 ↗
61. 10.1038/s41419-023-05956-010.1038/s41419-023-05956-0 ↗
62. 10.1038/s41467-023-39901-810.1038/s41467-023-39901-8 ↗