journal article·2025-05-06

Nanotherapeutic Wee1 Inhibition Sensitizes Tumor Ferroptosis to Promote Cancer Immunotherapy and Abscopal Effect

Peijie Zhou, Ruijie Huang, Yong Cheng, Yidong Yang, Dong Qian, Xin Ming, Andrew Z. Wang, Xiaoyuan Chen, Yuanzeng Min

ACS Nano· Volume 19· Issue 17
Publisher page

Abstract

The major issue with cancer immunotherapy is the low response rate. So, development of therapeutics enhancing immune responses is an urgent need. Tumor ferroptosis could produce immunogenic cancer cell death, which may improve cancer immunotherapy. However, current ferroptosis inducers may be limited to specific genetic backgrounds of cancer cells. Therefore, sensitization to ferroptosis inducers has also been highly pursued. Here, we found that Wee1 expression was negatively associated with drug sensitivity and positively correlated with an immunosuppressive microenvironment. Further investigation demonstrated that Wee1 inhibition could result in changes of ferroptosis and iron ion homeostasis, regardless of p53 status. Our in vitro results demonstrated the underlying mechanism that Wee1 inhibition primed cancer cells to ferroptosis through mitochondria reactive oxygen species and labile iron-dependent pathways. In order to decrease side effects, we developed an acidic responsive nanoformulation of the Wee1 inhibitor, which can sensitize tumor ferroptosis in vivo and also improve the response of cancer immunotherapy. Combining immunotherapy, nanotherapeutic Wee1 inhibition also produced abscopal effect with up to 55% mice cured that has not been seen before. In summary, nanotherapeutic Wee1 inhibition sensitized ferroptosis to enhance cancer immunotherapy and abscopal effect.
Source: openalex_inverted_index · Quality: baseline

Research context

OpenAlex topics: Ferroptosis and cancer prognosis · RNA modifications and cancer · Cancer Immunotherapy and Biomarkers

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

Affiliations

Department of Radiation Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine

University of Science and Technology of China

Department of Chemistry

School of Physical Sciences and Ion Medical Research Institute

Department of Cancer Biology and Department of Biomedical Engineering

Wake Forest University School of Medicine

Department of Radiation Oncology

Simmons Comprehensive Cancer Center, UT Southwestern Medical Center

Departments of Diagnostic Radiology, Surgery, Chemical and Biomolecular Engineering, and Biomedical Engineering, Yong Loo Lin School of Medicine and College of Design and Engineering

National University of Singapore

Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine

Nanomedicine Translational Research Program, Yong Loo Lin School of Medicine

Department of Endocrinology, Division of Life Sciences and Medicine

The First Affiliated Hospital of USTC, University of Science and Technology of China

Funding

University of Science and Technology of China · National Medical Research Council · Ministry of Education - Singapore · National Research Foundation of Korea · National University of Singapore · National Natural Science Foundation of China

References (61)

Show source-provided references
1. 10.1126/science.124948110.1126/science.1249481 ↗
2. 10.1056/NEJMoa120069410.1056/NEJMoa1200694 ↗
3. 10.1056/NEJMoa130513310.1056/NEJMoa1305133 ↗
4. 10.1056/NEJMoa100346610.1056/NEJMoa1003466 ↗
5. 10.1056/NEJMoa120069010.1056/NEJMoa1200690 ↗
6. 10.1056/NEJMoa130236910.1056/NEJMoa1302369 ↗
7. 10.1056/NEJMoa150182410.1056/NEJMoa1501824 ↗
8. 10.1016/j.cell.2017.01.01710.1016/j.cell.2017.01.017 ↗
9. 10.1038/d41573-020-00204-y10.1038/d41573-020-00204-y ↗
10. 10.1038/d41573-019-00182-w10.1038/d41573-019-00182-w ↗
11. 10.1002/advs.20200304910.1002/advs.202003049 ↗
12. 10.1016/j.ccell.2019.05.00110.1016/j.ccell.2019.05.001 ↗
13. 10.1200/JCO.19.0073010.1200/JCO.19.00730 ↗
14. 10.1016/S0140-6736(20)32554-X10.1016/S0140-6736(20)32554-X ↗
15. 10.1200/JCO.2014.60.400910.1200/JCO.2014.60.4009 ↗
16. 10.1038/s41568-022-00459-010.1038/s41568-022-00459-0 ↗
17. 10.1038/s41580-020-00324-810.1038/s41580-020-00324-8 ↗
18. 10.1038/s41467-022-31218-210.1038/s41467-022-31218-2 ↗
19. 10.1038/nrc349510.1038/nrc3495 ↗
20. 10.1002/hep4.201210.1002/hep4.2012 ↗
21. 10.1126/sciadv.abl892010.1126/sciadv.abl8920 ↗
22. 10.1038/s41420-022-01297-710.1038/s41420-022-01297-7 ↗
23. 10.1158/0008-5472.CAN-20-347710.1158/0008-5472.CAN-20-3477 ↗
24. 10.1038/nnano.2016.16410.1038/nnano.2016.164 ↗
25. 10.1021/acsnano.8b0586010.1021/acsnano.8b05860 ↗
26. 10.1016/j.ccell.2018.03.02210.1016/j.ccell.2018.03.022 ↗
27. 10.1158/2159-8290.CD-21-105910.1158/2159-8290.CD-21-1059 ↗
28. 10.1016/j.cell.2011.02.01310.1016/j.cell.2011.02.013 ↗
29. 10.1016/j.bbadis.2024.16745510.1016/j.bbadis.2024.167455 ↗
30. 10.1007/s11427-023-2589-110.1007/s11427-023-2589-1 ↗
31. 10.1038/s41422-019-0263-310.1038/s41422-019-0263-3 ↗
32. 10.1007/s11912-021-01098-810.1007/s11912-021-01098-8 ↗
33. 10.1038/nature2300710.1038/nature23007 ↗
34. 10.1016/j.celrep.2022.11081410.1016/j.celrep.2022.110814 ↗
35. 10.1080/15548627.2020.173944710.1080/15548627.2020.1739447 ↗
36. 10.1002/cyto.a.2049110.1002/cyto.a.20491 ↗
37. 10.1016/j.cell.2020.04.03910.1016/j.cell.2020.04.039 ↗
38. 10.1073/pnas.201715211710.1073/pnas.2017152117 ↗
39. 10.1016/j.celrep.2017.02.05410.1016/j.celrep.2017.02.054 ↗
40. 10.1038/cddis.2017.13310.1038/cddis.2017.133 ↗
41. 10.1080/15548627.2022.208486210.1080/15548627.2022.2084862 ↗
42. 10.1002/advs.20200468010.1002/advs.202004680 ↗
43. 10.3389/fonc.2020.0047610.3389/fonc.2020.00476 ↗
44. 10.1200/JCO.20.0316710.1200/JCO.20.03167 ↗
45. 10.1158/1078-0432.CCR-19-347010.1158/1078-0432.CCR-19-3470 ↗
46. 10.1038/s41551-024-01178-710.1038/s41551-024-01178-7 ↗
47. 10.1126/sciadv.ade144410.1126/sciadv.ade1444 ↗
48. 10.1038/s41568-021-00339-z10.1038/s41568-021-00339-z ↗
49. 10.1038/s41586-019-1170-y10.1038/s41586-019-1170-y ↗
50. 10.1002/anie.20221705510.1002/anie.202217055 ↗
51. 10.1038/nrclinonc.2016.21110.1038/nrclinonc.2016.211 ↗
52. 10.1038/nrc.2018.610.1038/nrc.2018.6 ↗
53. 10.1038/nature1429210.1038/nature14292 ↗
54. 10.1056/NEJMoa111282410.1056/NEJMoa1112824 ↗
55. 10.1038/nnano.2017.11310.1038/nnano.2017.113 ↗
56. 10.1073/pnas.191510811610.1073/pnas.1915108116 ↗
57. 10.1016/j.ccr.2010.08.01110.1016/j.ccr.2010.08.011 ↗
58. 10.1158/1078-0432.CCR-17-280510.1158/1078-0432.CCR-17-2805 ↗
59. 10.1016/j.biomaterials.2020.12062910.1016/j.biomaterials.2020.120629 ↗
60. 10.1158/1535-7163.MCT-12-073510.1158/1535-7163.MCT-12-0735 ↗
61. 10.1016/j.ijrobp.2022.07.183210.1016/j.ijrobp.2022.07.1832 ↗