Scholarlink

<p>Myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment (TME) limit the efficacy of adoptive T cell therapies, highlighting the need to overcome tumor-associated immunosuppression. Sphingosine-1-phosphate (S1P), is an abundant signaling lipid in the TME. Here, we show that inhibition of sphingosine kinase-2 (SphK2), the enzyme generating S1P in MDSCs, reduces the suppressive activity of monocytic MDSCs (M-MDSCs) while promoting their differentiation toward a mature, immunogenic phenotype characterized by enhanced antigen presentation. Pharmacological SphK2 inhibition enhances the response to anti–PD–1 therapy in preclinical models of checkpoint-resistant breast, bladder, and melanoma cancers by mitigating MDSC-mediated suppression and limiting tumor progression. Mechanistically, S1P directly binds acetyl-CoA carboxylase-1 (ACC1) to inhibit its activity, thereby rewiring fatty-acid metabolism. Lowering intracellular S1P restores ACC activity, promotes phosphatidylcholine synthesis, and reduces MDSC immunosuppression. These findings identify the SphK2–ACC–phospholipid axis as a metabolic checkpoint controlling the immunogenicity of MDSCs and a potential therapeutic target for enhancing cancer immunotherapy.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Sphingosine kinase-2 inhibition promotes immunogenic differentiation of myeloid-derived suppressor cells through an Acetyl-CoA carboxylase-phosphatidylcholine axis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年6月2日

查看全文
  • Paramita Chakraborty,
  • Shilpak Chatterjee,
  • Mohamed Faisal Kassir,
  • Wyatt Wofford,
  • Seungho Choi,
  • Natalia Oleinik,
  • Ozge Saatci,
  • Odai Darawshi,
  • Satyajit Das,
  • Nathaniel Oberhoeltzer,
  • Anupam Gautam,
  • Stephanie Mills,
  • Reid DeMass,
  • Zacharia Hedley,
  • Yueying Liu,
  • Rasesh Y. Parikh,
  • Sandip Paul,
  • Souvik Seal,
  • Charles D. Smith,
  • Michael B. Lilly,
  • Vamsi K. Gangaraju,
  • Yuri Peterson,
  • Meenal Mehrotra,
  • Elizabeth Hill,
  • Ozgur Sahin,
  • Norbert Leitinger,
  • Paulo C. Rodriguez,
  • Besim Ogretmen,
  • Shikhar Mehrotra

摘要

Myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment (TME) limit the efficacy of adoptive T cell therapies, highlighting the need to overcome tumor-associated immunosuppression. Sphingosine-1-phosphate (S1P), is an abundant signaling lipid in the TME. Here, we show that inhibition of sphingosine kinase-2 (SphK2), the enzyme generating S1P in MDSCs, reduces the suppressive activity of monocytic MDSCs (M-MDSCs) while promoting their differentiation toward a mature, immunogenic phenotype characterized by enhanced antigen presentation. Pharmacological SphK2 inhibition enhances the response to anti–PD–1 therapy in preclinical models of checkpoint-resistant breast, bladder, and melanoma cancers by mitigating MDSC-mediated suppression and limiting tumor progression. Mechanistically, S1P directly binds acetyl-CoA carboxylase-1 (ACC1) to inhibit its activity, thereby rewiring fatty-acid metabolism. Lowering intracellular S1P restores ACC activity, promotes phosphatidylcholine synthesis, and reduces MDSC immunosuppression. These findings identify the SphK2–ACC–phospholipid axis as a metabolic checkpoint controlling the immunogenicity of MDSCs and a potential therapeutic target for enhancing cancer immunotherapy.