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; Weiping Zou

doi:10.1038/s41467-025-58552-5

Palmitoylation prevents B7-H4 lysosomal degradation sustaining tumor immune evasion

Nat Commun. 2025 May 8;16(1):4254. doi: 10.1038/s41467-025-58552-5.

Authors

Yijian Yan^#^{1

2}, Jiali Yu^#^{1

2}, Weichao Wang^{1

2}, Ying Xu^{1

2}, Kole Tison^{1

2}, Rongxin Xiao^{1

2}, Sara Grove^{1

2}, Shuang Wei^{1

2}, Linda Vatan^{1

2}, Max Wicha³, Ilona Kryczek^{1

2}, Weiping Zou^{4

5

6

7

8}

Affiliations

¹ Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA.
² Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA.
³ Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
⁴ Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA. wzou@umich.edu.
⁵ Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA. wzou@umich.edu.
⁶ Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA. wzou@umich.edu.
⁷ Graduate Program in Immunology, University of Michigan, Ann Arbor, MI, USA. wzou@umich.edu.
⁸ Graduate Program in Cancer Biology, University of Michigan, Ann Arbor, MI, USA. wzou@umich.edu.

^# Contributed equally.

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.

MeSH terms

Acyltransferases / genetics
Acyltransferases / metabolism
Aminopyridines / pharmacology
Animals
Benzimidazoles / pharmacology
Breast Neoplasms* / drug therapy
Breast Neoplasms* / immunology
Breast Neoplasms* / metabolism
Breast Neoplasms* / pathology
Cell Line, Tumor
Female
Humans
Lipoylation* / drug effects
Lymphocyte Activation / drug effects
Lysosomes* / drug effects
Lysosomes* / metabolism
Mice
Proteolysis / drug effects
T-Lymphocytes / drug effects
T-Lymphocytes / immunology
Tumor Escape* / drug effects
Tumor Escape* / immunology
Tumor Microenvironment / drug effects
Tumor Microenvironment / immunology
V-Set Domain-Containing T-Cell Activation Inhibitor 1* / genetics
V-Set Domain-Containing T-Cell Activation Inhibitor 1* / immunology
V-Set Domain-Containing T-Cell Activation Inhibitor 1* / metabolism

Substances

Acyltransferases
V-Set Domain-Containing T-Cell Activation Inhibitor 1
Aminopyridines
Benzimidazoles
abemaciclib
VTCN1 protein, human

Abstract

MeSH terms

Substances

Grants and funding