2. Academic Validation
  3. Sphingolipid synthesis in tumor-associated macrophages confers immunotherapy resistance in hepatocellular carcinoma

Sphingolipid synthesis in tumor-associated macrophages confers immunotherapy resistance in hepatocellular carcinoma

  • Sci Adv. 2025 May 23;11(21):eadv0558. doi: 10.1126/sciadv.adv0558.
Xiaozhen Zhang 1 2 3,  Mengyi Lao 2 4,  Kang Sun 1 2 3,  Hanshen Yang 1 2 3,  Lihong He 1 2 3,  Xinyuan Liu 1 2 3,  Linyue Liu 1 2 3,  Sirui Zhang 1 2 3,  Chengxiang Guo 2 5,  Sicheng Wang 1 2 3,  Jiatao Shi 1 2 3,  Xiaoyu Zhang 1 2 3,  Daqian Xu 1 2 3,  Xiongbin Lu 1 2 3,  Xueli Bai 1 2 3,  Tingbo Liang 1 2 3
Affiliations

Affiliations

  • 1 Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China.
  • 2 Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang, China.
  • 3 MOE Joint International Research Laboratory of Pancreatic Diseases, Hangzhou, China.
  • 4 Department of Breast, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China.
  • 5 Department of Oncology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang, China.
PMID: 40397754 DOI: 10.1126/sciadv.adv0558
Abstract

Dysregulated metabolism of immune cells in the tumor microenvironment leads to immune evasion and tumor progression. As a major cell component in the tumor, the metabolic reprogramming of tumor-associated macrophages (TAMs) creates an immunosuppressive microenvironment in hepatocellular carcinoma (HCC). Our study found that sphingolipid (particularly, sphingosine-1-phosphate or S1P) levels are a clinical indicator for prognosis and immunotherapy response in patients with HCC. S1P primarily derived from TAMs, where NIMA-related kinase 2 (NEK2) plays a key role in controlling the activity of serine palmitoyl-CoA transferase, a rate-limiting enzyme in S1P biosynthesis. The S1P produced by NEK2hi TAMs promotes hepatic tumor progression and confers immunotherapy resistance. Targeting S1P synthesis with a NEK2 Inhibitor or S1P antagonist disrupted the immunosuppressive function of macrophages, shifted regulatory T cells (Tregs) to TH17 cells, and increased the number and activity of tumor-infiltrating T effectors, thereby enhancing antitumor efficacy in synergy with immune checkpoint blockade therapy.

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