Author
Listed:
- Yijian Yan
(University of Michigan Medical School
University of Michigan Rogel Cancer Center)
- Jiali Yu
(University of Michigan Medical School
University of Michigan Rogel Cancer Center)
- Weichao Wang
(University of Michigan Medical School
University of Michigan Rogel Cancer Center)
- Ying Xu
(University of Michigan Medical School
University of Michigan Rogel Cancer Center)
- Kole Tison
(University of Michigan Medical School
University of Michigan Rogel Cancer Center)
- Rongxin Xiao
(University of Michigan Medical School
University of Michigan Rogel Cancer Center)
- Sara Grove
(University of Michigan Medical School
University of Michigan Rogel Cancer Center)
- Shuang Wei
(University of Michigan Medical School
University of Michigan Rogel Cancer Center)
- Linda Vatan
(University of Michigan Medical School
University of Michigan Rogel Cancer Center)
- Max Wicha
(University of Michigan Medical School)
- Ilona Kryczek
(University of Michigan Medical School
University of Michigan Rogel Cancer Center)
- Weiping Zou
(University of Michigan Medical School
University of Michigan Rogel Cancer Center
University of Michigan Medical School
University of Michigan)
Abstract
B7-H4 functions as an immune checkpoint in the tumor microenvironment (TME). However, the post-translational modification (PTM) of B7-H4 and its translational potential in cancer remains incompletely understood. We find that ZDHHC3, a zinc finger DHHC-type palmitoyltransferase, palmitoylates B7-H4 at Cys130 in breast cancer cells, preventing its lysosomal degradation and sustaining B7-H4-mediated immunosuppression. Knockdown of ZDHHC3 in tumors results in robust anti-tumor immunity and reduces tumor progression in murine models. Moreover, abemaciclib, a CDK4/6 inhibitor, primes lysosome activation and promotes lysosomal degradation of B7-H4 independently of the tumor cell cycle. Treatment with abemaciclib results in T cell activation and mitigates B7-H4-mediated immune suppression via inducing B7-H4 degradation in preclinical tumor models. Thus, B7-H4 palmitoylation is an important PTM controlling B7-H4 protein stability and abemaciclib may be repurposed to promote B7-H4 degradation, thereby treating patients with B7-H4 expressing tumors.
Suggested Citation
Yijian Yan & Jiali Yu & Weichao Wang & Ying Xu & Kole Tison & Rongxin Xiao & Sara Grove & Shuang Wei & Linda Vatan & Max Wicha & Ilona Kryczek & Weiping Zou, 2025.
"Palmitoylation prevents B7-H4 lysosomal degradation sustaining tumor immune evasion,"
Nature Communications, Nature, vol. 16(1), pages 1-14, December.
Handle:
RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58552-5
DOI: 10.1038/s41467-025-58552-5
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