Inhibition of salt-inducible kinases reprograms T cells and antitumor immunity in ovarian cancer PMID: 42162294

ADC Targets in Oncology

2026-04-10

Inhibition of salt-inducible kinases reprograms T cells and antitumor immunity in ovarian cancer

Nat Immunol. 2026 Jun;27(6):1237-1252. doi: 10.1038/s41590-026-02512-8.

Han Dong ^# ¹ ² ³ , Arindam Ray ^# ⁴ ⁵ , Lara K Rotter ⁴ ⁵ , Jinhua Wang ⁶ ⁷ , Isabella Grabski ⁸ , Heemaja Mewada ⁴ ⁹ , Lulu Wang ⁴ , Kun Huang ¹⁰ , Ye Tian ⁴ ⁵ , Maxime Meylan ⁴ ⁵ , Graham Barlow ⁴ ⁵ , Chenyang Yu ⁴ , Mahesh Raundhal ⁴ , Sung-Hee Yoon ¹¹ , Shreya Nakhawa ¹⁰ , Liya Ding ⁷ ¹² , Jean J Zhao ⁶ ⁷ , Ursula A Matulonis ¹³ , Marc Foretz ¹⁴ , Kai W Wucherpfennig ⁴ ⁵ ¹⁵ , Rafael A Irizarry ⁸ ¹⁶ , Marc N Wein ¹¹ ¹⁷ ¹⁸ , Laurie H Glimcher ¹⁹ ²⁰

Affiliations

1. Shanghai Immune Therapy Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. [email protected].
2. Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].
3. Department of Immunology, Harvard Medical School, Boston, MA, USA. [email protected].
4. Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.
5. Department of Immunology, Harvard Medical School, Boston, MA, USA.
6. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
7. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
8. Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
9. Department of Microbiology, New York University Grossman School of Medicine, New York, NY, USA.
10. Molecular Imaging Core, Dana-Farber Cancer Institute, Boston, MA, USA.
11. Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
12. Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
13. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
14. Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France.
15. Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.
16. Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA.
17. Broad Institute of MIT and Harvard, Cambridge, MA, USA.
18. Harvard Stem Cell Institute, Cambridge, MA, USA.
19. Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].
20. Department of Immunology, Harvard Medical School, Boston, MA, USA. [email protected].
# Contributed equally.

Abstract

Patients with metastatic high-grade serous ovarian carcinoma are often unresponsive to immunotherapies; here we identify salt-inducible kinases (SIKs) as key drivers of immunosuppression. Human T cells in the presence of patient ascites express high levels of SIK and the upstream kinase LKB1, whereas SIK inhibition reprograms human T cells and strongly activates antitumor responses. In syngeneic mice with resistant high-grade serous ovarian carcinoma, genetic ablation and pharmaceutical inhibition of SIK consistently demonstrated therapeutic efficacy and survival advantages, and combination of PD-1 blockade with SIK inhibition further extended survival. We identified a major role of T cell-intrinsic SIK2 and -3 signaling in driving immunosuppression in part by TXNIP induction and LYST suppression. Multi-omics analyses on SIK inhibitor therapy revealed reduced disease progression, increased T cell infiltration with enhanced cytotoxicity and effector cytokine IFN-γ, and a shift from immunosuppressive to immunostimulatory cellular niche. We propose SIK inhibitors as a new immunotherapy.