PROTAC technology for sensitizing melanoma to immune checkpoint therapy.
6 affiliations
- 1Department of Dermatology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, China.
- 2Physical Examination Center, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, Liaoning, China.
- 3Department of First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310000, China.
- 4Department of Clinical Medicine, He University, Shenyang, Liaoning, 110163, China.
- 5Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, China. [email protected].
- 6The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, 310003, China. [email protected].
Abstract
Melanoma remains one of the most aggressive malignancies, with limited response to immune checkpoint inhibitors (ICIs) due to primary or acquired resistance. Proteolysis-targeting chimeras (PROTACs) have emerged as a novel therapeutic modality that induces selective degradation of target proteins via the ubiquitin-proteasome system, offering distinct advantages over conventional inhibitors. This review summarizes the design principles and molecular mechanisms of PROTACs, and highlights their emerging role in sensitizing melanoma to immunotherapy. Specifically, PROTACs can restore tumor antigen presentation, reprogram the immunosuppressive tumor microenvironment by targeting regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages, and suppress key oncogenic signaling pathways. We also discuss combination strategies with PD-1/PD-L1 and CTLA-4 blockade, as well as current challenges including poor cell permeability, off-target effects, and acquired resistance. Finally, future perspectives on rational design, tissue-specific delivery systems, and clinical translation are addressed.
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BibTeX
@article{zhou2026protac,
title = {{PROTAC technology for sensitizing melanoma to immune checkpoint therapy.}},
author = {Qiujun Zhou and Xiaowei Zhang and Chenlu Zhao and Difei Chen and Chen Chu and Xiaoliang Jin},
journal = {Journal of experimental \& clinical cancer research : CR},
year = {2026},
month = aug,
doi = {10.1186/s13046-026-03799-z},
url = {https://europepmc.org/article/MED/42958414},
note = {CC BY},
}
RIS
TY - JOUR
TI - PROTAC technology for sensitizing melanoma to immune checkpoint therapy.
AU - Qiujun Zhou
AU - Xiaowei Zhang
AU - Chenlu Zhao
AU - Difei Chen
AU - Chen Chu
AU - Xiaoliang Jin
PY - 2026
DA - 2026/08/03
JO - Journal of experimental & clinical cancer research : CR
DO - 10.1186/s13046-026-03799-z
UR - https://europepmc.org/article/MED/42958414
AB - Melanoma remains one of the most aggressive malignancies, with limited response to immune checkpoint inhibitors (ICIs) due to primary or acquired resistance. Proteolysis-targeting chimeras (PROTACs) have emerged as a novel therapeutic modality that induces selective degradation of target proteins via the ubiquitin-proteasome system, offering distinct advantages over conventional inhibitors. This review summarizes the design principles and molecular mechanisms of PROTACs, and highlights their emerging role in sensitizing melanoma to immunotherapy. Specifically, PROTACs can restore tumor antigen presentation, reprogram the immunosuppressive tumor microenvironment by targeting regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages, and suppress key oncogenic signaling pathways. We also discuss combination strategies with PD-1/PD-L1 and CTLA-4 blockade, as well as current challenges including poor cell permeability, off-target effects, and acquired resistance. Finally, future perspectives on rational design, tissue-specific delivery systems, and clinical translation are addressed.
SN - 0392-9078
SN - 1756-9966
ER -