DataVXAdvanced SciencePaper
journal article·2026-03Open access

TOPK Inhibition Promotes Anti‐Tumor Immunity Via eIF4F Complex Mediated STAT1 Translation in Gastric Cancer

Junbing Chen, Longtao Huangfu, Gangjian Wang, Xueying Wang, Huanbo Zhu, Qian Yao, Cong Chen, Xiaohuan Tang, Ting Guo, Biao Fan, Xingyang Liu, Qingda Li, Zining Liu, Ying Hu, Tianze Sun, Jiafu Ji, Xiaofang Xing

Advanced Science· Volume 13· Issue 13
Publisher pageOpen full text
Source abstract

Abstract

Abstract Immune checkpoint blockade‐directed immunotherapy emerges as a revolutionary therapy in gastric cancer (GC). However, the proportion of patients who can benefit from it and its overall efficacy remain limited. Here the aim is to identify key dual‐function targets that both inhibit proliferation and suppress immune evasion. Using whole genome‐wide CRISPR‐Cas9‐based screening, the serine/threonine kinase T‐lymphokine‐activated killer cell‐originated protein kinase (TOPK) is identified as a key regulator of PD‐L1 in gastric cancer upon IFN‐γ stimulation. Mechanical study is performed to explore the role of TOPK in promoting GC malignancy and immune evasion in vitro and vivo. Higher TOPK levels in tumor tissues are observed, correlated with clinical stages, efficacy and survival. Upon IFN‐γ stimulation, TOPK phosphorylates eIF4F complex component eIF4A1 to increase its unwinding activity of STAT1 mRNA, enhancing STAT1 translation efficiency. This process leads to adaptive overexpression of PD‐L1 and IDO1, resulting in immunometabolic suppression through PD‐L1‐mediated inhibition, IDO1‐induced tryptophan depletion and kynurenine production. TOPK inhibitors reshape tumor immunometabolic microenvironment to trigger anti‐tumor immunity in GC. The IFN‐γ‐TOPK‐eIF4F‐STAT1‐PD‐L1/IDO1 axis as a crucial regulator of the tumor immunometabolic microenvironment and provide novel insights into the combination of targeted therapy and immunotherapy for GC treatment.
Source: crossref · Quality: baseline

Research context

OpenAlex topics: FOXO transcription factor regulation · Signaling Pathways in Disease · Cancer Mechanisms and Therapy

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

Affiliations

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

Department of Hepatobiliary Surgery & Liver Transplantation Liver Cancer Institute Zhongshan Hospital Fudan University Key Laboratory of Carcinogenesis and Cancer Invasion Ministry of Education Shanghai 200032 China

Department of Gastrointestinal Surgery Peking University Cancer Hospital and Institute Beijing 100142 China

Program in MPE Molecular Pathological Epidemiology Department of Pathology Brigham and Women's Hospital Harvard Medical School Boston MA 02215 USA

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing) Laboratory of Molecular Oncology Peking University Cancer Hospital & Institute Beijing 100142 China

Department of Gynecologic Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital Chinese Academy of Medical Sciences & Peking Union Medical College Beijing 100021 China

Biological Sample Bank Peking University Cancer Hospital & Institute Fu‐Cheng Road Beijing 100142 China

State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers Beijing Key Laboratory of Carcinogenesis and Translational Research Division of Gastrointestinal Cancer Translational Research Laboratory Peking University Cancer Hospital & Institute Beijing 100142 China

Funding

National Natural Science Foundation of China · Natural Science Foundation of Beijing Municipality · China Postdoctoral Science Foundation

References (47)

Show source-provided references
1. 10.1038/s41571-021-00492-210.1038/s41571-021-00492-2 ↗
2. 10.3390/cancers1309223210.3390/cancers13092232 ↗
3. 10.1186/s13046-023-02652-x10.1186/s13046-023-02652-x ↗
4. 10.1126/scitranslmed.301027710.1126/scitranslmed.3010277 ↗
5. 10.1002/jcp.3013410.1002/jcp.30134 ↗
6. 10.1111/1759-7714.1376810.1111/1759-7714.13768 ↗
7. 10.3389/fgene.2021.64735310.3389/fgene.2021.647353 ↗
8. 10.3389/fmolb.2021.78537010.3389/fmolb.2021.785370 ↗
9. 10.1186/s12957-021-02479-w10.1186/s12957-021-02479-w ↗
10. 10.3390/biomedicines1002029910.3390/biomedicines10020299 ↗
11. 10.1016/j.canlet.2022.21581210.1016/j.canlet.2022.215812 ↗
12. 10.1016/j.ccell.2023.12.01010.1016/j.ccell.2023.12.010 ↗
13. 10.1016/j.prp.2023.15463610.1016/j.prp.2023.154636 ↗
14. 10.4251/wjgo.v14.i1.21610.4251/wjgo.v14.i1.216 ↗
15. 10.1038/s41591-018-0217-110.1038/s41591-018-0217-1 ↗
16. 10.1038/s41591-018-0321-210.1038/s41591-018-0321-2 ↗
17. 10.1038/s41568-021-00380-y10.1038/s41568-021-00380-y ↗
18. 10.1038/nature2364310.1038/nature23643 ↗
19. 10.1073/pnas.212054011910.1073/pnas.2120540119 ↗
20. 10.1182/blood.201900104310.1182/blood.2019001043 ↗
21. 10.1038/s41392-023-01450-310.1038/s41392-023-01450-3 ↗
22. 10.1186/s12929-017-0317-010.1186/s12929-017-0317-0 ↗
23. 10.1016/j.bcp.2022.11494010.1016/j.bcp.2022.114940 ↗
24. 10.1007/s00432-020-03390-910.1007/s00432-020-03390-9 ↗
25. 10.1136/jitc-2020-00137210.1136/jitc-2020-001372 ↗
26. 10.1016/j.cellimm.2018.01.01410.1016/j.cellimm.2018.01.014 ↗
27. 10.1016/j.bbcan.2022.18873810.1016/j.bbcan.2022.188738 ↗
28. 10.1038/s41591-018-0101-z10.1038/s41591-018-0101-z ↗
29. 10.1158/1078-0432.CCR-20-116310.1158/1078-0432.CCR-20-1163 ↗
30. 10.1016/S0140-6736(16)32455-210.1016/S0140-6736(16)32455-2 ↗
31. 10.1038/s41416-021-01488-610.1038/s41416-021-01488-6 ↗
32. 10.1038/cmi.2017.14310.1038/cmi.2017.143 ↗
33. 10.3390/ijms2112440210.3390/ijms21124402 ↗
34. 10.1038/s41586-022-05575-310.1038/s41586-022-05575-3 ↗
35. 10.1016/S1470-2045(23)00411-410.1016/S1470-2045(23)00411-4 ↗
36. 10.1016/j.celrep.2017.11.05210.1016/j.celrep.2017.11.052 ↗
37. 10.1038/s41591-020-0839-y10.1038/s41591-020-0839-y ↗
38. 10.1038/s41591-019-0654-510.1038/s41591-019-0654-5 ↗
39. 10.6004/jnccn.2022.000810.6004/jnccn.2022.0008 ↗
40. 10.1007/s00432-022-04408-010.1007/s00432-022-04408-0 ↗
41. 10.3390/life1201008110.3390/life12010081 ↗
42. 10.1111/bcpt.1400210.1111/bcpt.14002 ↗
43. 10.1007/s10120-018-0880-410.1007/s10120-018-0880-4 ↗
44. 10.1038/s41392-022-01190-w10.1038/s41392-022-01190-w ↗
45. 10.1038/s41467-022-33285-x10.1038/s41467-022-33285-x ↗
46. 10.1111/odi.1453310.1111/odi.14533 ↗
47. 10.1038/s41596-018-0113-710.1038/s41596-018-0113-7 ↗