Citation: Xiaopeng Han, Jiayin Li, Fei Li, Zhongyue Yuan, Hao Li, Lei Yang, Yan-Ming Xia, Chao Teng, Chao Qin, Lifang Yin. ROS-sensitive dihydroartemisinin prodrug amplify chemo-immunotherapy efficacy of doxorubicin by coordinating robust tumor cell immunogenic cell death and PD-L1 blockade[J]. Chinese Chemical Letters, ;2026, 37(2): 111335. doi: 10.1016/j.cclet.2025.111335 shu

ROS-sensitive dihydroartemisinin prodrug amplify chemo-immunotherapy efficacy of doxorubicin by coordinating robust tumor cell immunogenic cell death and PD-L1 blockade

Xiaopeng Han ^{a, 1} ,
Jiayin Li ^{a, 1} ,
Fei Li ^{a, 1} ,
Zhongyue Yuan ^{a, b} ,
Hao Li ^a ,
Lei Yang ^a ,
Yan-Ming Xia ^a ,
Chao Teng ^{d, e} ,
Chao Qin ^{a, *,} ,
Lifang Yin ^{a, c, *,}

a.
Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China
b.
Department of Industrial and Molecular Pharmaceutics, Purdue University, West Lafayette, IN 47907, United States
c.
Key Laboratory of Drug Quality Control and Pharmacovigilance, China Pharmaceutical University, China; State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, China
d.
School of Pharmacy, Fujian Medical University, Fuzhou 350122, China
e.
Fujian Key Laboratory of Natural Medicine Pharmacology, School of Pharmacy, Fujian Medical University, Fuzhou 350122, China

nada77@163.com

lifangyin_@163.com

Received Date: 18 February 2025
Revised Date: 15 May 2025
Accepted Date: 15 May 2025
Available Online: 16 May 2025

Figures(6)

Doxorubicin (DOX) is known to elicit potent antitumor immune responses through the induction of immunogenic cell death (ICD). However, its therapeutic efficacy is undermined by the adaptive upregulation of programmed cell death ligand 1 (PD-L1), which hijacked the antitumor immunity. In this study, we developed a reactive oxygen species (ROS)-responsive dihydroartemisinin (DHA) prodrug to facilitate the delivery of DOX via hydrophobic and electrostatic interactions. Upon internalization by tumor cells, the nanoparticles (NPs) preferentially accumulated in endoplasmic reticulum (ER), exacerbating ER stress and amplifying ICD to enhance tumor immunogenicity. Simultaneously, the oxidative intracellular environment trigged the degradation of NPs, releasing DHA, which downregulated PD-L1 by disrupting signal transducer and activator of transcription 3 (STAT3) phosphorylation and inactivating the nuclear factor kappa-B (NF-κB) pathway. Consequently, the effective PD-L1 blockade and robust ICD response, synergistically inhibited breast cancer progression, significantly enhancing the chemo-immunotherapy efficacy of doxorubicin.
- ROS-sensitive-prodrug,
- Dihydroartemisinin,
- Doxorubicin,
- Chemo-immunotherapy,
- Immunogenic cell death,
- PD-L1 blockade
1. [1]
  C. Galassi, V. Klapp, T. Yamazaki, L. Galluzzi, Immunol. Rev. 321 (2024) 20–32. doi: 10.1111/imr.13271
2. [2]
  J. Liu, P. Liu, J. Duan, et al., Chin. Chem. Lett. 35 (2024) 109632. doi: 10.1016/j.cclet.2024.109632
3. [3]
  J.Y. Zhou, Q.H. Shen, X.J. Hong, et al., Chem. Eng. J. 474 (2023) 145516. doi: 10.1016/j.cej.2023.145516
4. [4]
  S. Zhang, J. Wang, Z. Kong, et al., Biomaterials 282 (2022) 121433. doi: 10.1016/j.biomaterials.2022.121433
5. [5]
  X. Liu, Y. Lu, X. Li, L. Luo, J. You, J. Control. Release 365 (2024) 1058–1073. doi: 10.1016/j.jconrel.2023.11.058
6. [6]
  Y. Gao, R. Zhou, Q. Wang, et al., Chin. Chem. Lett. 35 (2024) 109521. doi: 10.1016/j.cclet.2024.109521
7. [7]
  X. Qiu, Y. Qu, B. Guo, et al., J. Control. Release 341 (2022) 498–510. doi: 10.1016/j.jconrel.2021.12.002
8. [8]
  M. Zhang, X. Jin, M. Gao, Y. Zhang, B.Z. Tang, Adv. Mater. 34 (2022) 2205701. doi: 10.1002/adma.202205701
9. [9]
  J. Li, S. Zhou, J. Yu, et al., J. Control. Release 335 (2021) 306–319. doi: 10.1016/j.jconrel.2021.05.040
10. [10]
  L. Zhang, N. Montesdeoca, J. Karges, H. Xiao, Angew. Chemie. Int. Ed. 62 (2023) e202300662. doi: 10.1002/anie.202300662
11. [11]
  Q. Liang, Y. Lan, Y. Li, et al., Eur. J. Pharm. Biopharm. 177 (2022) 260–272. doi: 10.1016/j.ejpb.2022.07.006
12. [12]
  S. Chen, D. Li, X. Du, et al., Nano Today 35 (2020) 100924. doi: 10.1016/j.nantod.2020.100924
13. [13]
  J. Liu, Z. Zhao, N. Qiu, et al., Nat. Commun. 12 (2021) 2425. doi: 10.1038/s41467-021-22407-6
14. [14]
  M. Barati, F. Mirzavi, A.R. Nikpoor, et al., Cancer Gene Ther. 29 (2022) 814–824. doi: 10.1038/s41417-021-00367-9
15. [15]
  C.D. Phung, H.T. Nguyen, J.Y. Choi, et al., J. Control. Release 315 (2019) 126–138. doi: 10.1016/j.jconrel.2019.10.047
16. [16]
  D. Liu, K. Li, L. Gong, L. Fu, D. Yang, Int. J. Pharm. 635 (2023) 122728. doi: 10.1016/j.ijpharm.2023.122728
17. [17]
  P. Sun, Z. Li, D. Zhang, et al., Chin. Chem. Lett. 35 (2024) 108346. doi: 10.1016/j.cclet.2023.108346
18. [18]
  H. Zhu, K. Ma, R. Ruan, et al., Chin. Chem. Lett. 35 (2024) 108536. doi: 10.1016/j.cclet.2023.108536
19. [19]
  Z. Zhou, W. Luo, C. Zheng, et al., Acta Pharm. Sin. B 14 (2024) 4087–4101. doi: 10.1016/j.apsb.2024.05.028
20. [20]
  N. Zhang, J. Li, W. Gao, et al., Mol. Pharm. 19 (2022) 3439–3449. doi: 10.1021/acs.molpharmaceut.2c00611
21. [21]
  Q. Li, C. Chen, J. Kong, et al., Acta Pharm. Sin. B 12 (2022) 2533–2549. doi: 10.1016/j.apsb.2021.11.005
22. [22]
  Y. Wang, P. Wang, W. Li, et al., Nano Today 56 (2024) 102305. doi: 10.1016/j.nantod.2024.102305
23. [23]
  B. Zhang, L. Li, M. Huang, et al., Nano Lett. 24 (2024) 3759–3767. doi: 10.1021/acs.nanolett.4c00300
24. [24]
  T. Liu, L. Li, S. Wang, et al., Nat. Commun. 13 (2022) 7228. doi: 10.1038/s41467-022-35033-7
25. [25]
  T. Hu, C. Shen, X. Wang, F. Wu, Z. He, Chin. Chem. Lett. 35 (2024) 109562. doi: 10.1016/j.cclet.2024.109562
26. [26]
  C. Ou, M. Xiao, X. Zheng, et al., Chin. Chem. Lett. 35 (2024) 109275. doi: 10.1016/j.cclet.2023.109275
27. [27]
  Y. Zheng, C. Qin, F. Li, et al., Biomater. Sci. 11 (2023) 3321–3334. doi: 10.1039/d2bm02032g
28. [28]
  X. Dai, X. Zhang, W. Chen, et al., Int. J. Biol. Sci. 17 (2021) 603–622. doi: 10.7150/ijbs.50364
29. [29]
  K.H. Wong, D. Yang, S. Chen, C. He, M. Chen, Asian J. Pharm. Sci. 17 (2022) 475–490.
30. [30]
  Z. Qiu, Z. Lu, J. Huang, et al., Biomaterials 303 (2023) 122392. doi: 10.1016/j.biomaterials.2023.122392
31. [31]
  H. Cai, L. Yan, N. Liu, et al., Biomed. Pharmacother. 123 (2020) 109790. doi: 10.1016/j.biopha.2019.109790
32. [32]
  X. Duan, C. Chan, W. Han, et al., Nat. Commun. 10 (2019) 1899. doi: 10.1038/s41467-019-09221-x
33. [33]
  K. Deng, B. Wu, C.X. Wang, et al., Adv. Healthc. Mater. 9 (2020) e2000533. doi: 10.1002/adhm.202000533
34. [34]
  S. Lu, R. Xia, J. Wang, et al., ACS Appl. Mater. Interfaces 13 (2021) 46291–46302. doi: 10.1021/acsami.1c12353
35. [35]
  J. Zhang, X. Sun, M. Xu, et al., Acta Biomater. 149 (2022) 307–320. doi: 10.3390/chemosensors10080307
36. [36]
  L. Chen, R. Xu, Y. Ding, et al., Eur. J. Med. Chem. 241 (2022) 114622. doi: 10.1016/j.ejmech.2022.114622
37. [37]
  M. Liu, Z. Cao, R. Zhang, et al., ACS Appl. Mater. Interfaces 13 (2021) 33874–33884. doi: 10.1021/acsami.1c08285
38. [38]
  X. Feng, T. Lin, D. Chen, et al., Acta Biomater. 160 (2023) 211–224. doi: 10.1016/j.actbio.2023.02.011
39. [39]
  J. Jeon, B. Yoon, A. Dey, et al., Biomaterials 295 (2023) 122064. doi: 10.1016/j.biomaterials.2023.122064
40. [40]
  M. Reda, W. Ngamcherdtrakul, M.A. Nelson, et al., Nat. Commun. 13 (2022) 4261. doi: 10.1038/s41467-022-31926-9
41. [41]
  F. Antonangeli, A. Natalini, M.C. Garassino, et al., Front. Immunol. 11 (2020) 584626. doi: 10.3389/fimmu.2020.584626
42. [42]
  J. An, M. Liu, L. Zhao, et al., Adv. Funct. Mater. 32 (2022) 2201275. doi: 10.1002/adfm.202201275
43. [43]
  S. Yin, Z. Chen, D. Chen, D. Yan, Theranostics 13 (2023) 1520–1544. doi: 10.7150/thno.80091
44. [44]
  C. Hu, X. He, Y. Chen, et al., Adv. Funct. Mater. 31 (2021) 2007149. doi: 10.1002/adfm.202007149
45. [45]
  H. Yamaguchi, J.M. Hsu, W.H. Yang, M.C. Hung, Nat. Rev. Clin. Oncol. 19 (2022) 287–305. doi: 10.1038/s41571-022-00601-9
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