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<p>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.</p>

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

  • 期刊论文

  • 发表日期：

    2026年5月20日

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  • Han Dong,
  • Arindam Ray,
  • Lara K. Rotter,
  • Jinhua Wang,
  • Isabella Grabski,
  • Heemaja Mewada,
  • Lulu Wang,
  • Kun Huang,
  • Ye Tian,
  • Maxime Meylan,
  • Graham Barlow,
  • Chenyang Yu,
  • Mahesh Raundhal,
  • Sung-Hee Yoon,
  • Shreya Nakhawa,
  • Liya Ding,
  • Jean J. Zhao,
  • Ursula A. Matulonis,
  • Marc Foretz,
  • Kai W. Wucherpfennig,
  • Rafael A. Irizarry,
  • Marc N. Wein,
  • Laurie H. Glimcher

摘要

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.