Palmitoylation prevents B7-H4 lysosomal degradation sustaining tumor immune evasion

Yijian Yan, Jiali Yu, Weichao Wang, Ying Xu, Kole Tison, Rongxin Xiao, Sara Grove, Shuang Wei, Linda Vatan, Max Wicha, Ilona Kryczek and Weiping Zou ()
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Yijian Yan: University of Michigan Medical School
Jiali Yu: University of Michigan Medical School
Weichao Wang: University of Michigan Medical School
Ying Xu: University of Michigan Medical School
Kole Tison: University of Michigan Medical School
Rongxin Xiao: University of Michigan Medical School
Sara Grove: University of Michigan Medical School
Shuang Wei: University of Michigan Medical School
Linda Vatan: University of Michigan Medical School
Max Wicha: University of Michigan Medical School
Ilona Kryczek: University of Michigan Medical School
Weiping Zou: University of Michigan Medical School

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-58552-5

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