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<p>Fatty acid (FA) oxidation plays an important role in T cell responses. However, whether DGAT1-mediated FA esterification to triacylglycerol also regulates T cell function remains unclear. Here we uncover a sexually dimorphic requirement for DGAT1 expression in CD8<sup>+</sup> tumour-infiltrating lymphocyte function. In female mice, T cell-specific <i>Dgat1</i> deficiency improves mitochondrial metabolic fitness and expands the pool of progenitor exhausted CD8<sup>+</sup> T (T<sub>ex</sub>) cells to sustain antitumour responses. In male mice, however, <i>Dgat1</i> deficiency leads to FA peroxidation, endoplasmic reticulum (ER) stress and CD8<sup>+</sup> T<sub>ex</sub> cell death. We show that these effects are mediated by androgen receptor (AR) signalling. Deletion of <i>Ar</i>, overexpression of glutathione peroxidase 4, or inhibition of ER stress-induced cell death rescues <i>Dgat1</i>-deficient CD8<sup>+</sup> T cell survival and promotes antitumour responses in male mice. Overall, this study suggests that DGAT1 detoxifies AR signalling in male mice to protect against ER stress-induced cell death and maintain T cell stemness, and uncovers sex-specific metabolic adaptations in the tumour microenvironment.</p>

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DGAT1 mediates sex-specific CD8+ T cell antitumour responses

  • 期刊论文

  • 发表日期：

    2026年3月20日

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  • Alaa Madi,
  • Hui Shi,
  • Min Su,
  • Ahmed Mady,
  • Boqiong Lv,
  • Haiyan Wang,
  • Bing Yang,
  • Zhenni Yan,
  • Xiaomeng Jin,
  • Lingling Wu,
  • Mengyue Lv,
  • Marvin Hering,
  • Sicong Ma,
  • Alessa Mieg,
  • Ferdinand Zettl,
  • Xin Yan,
  • Kerstin Mohr,
  • Nora Knabe,
  • Gernot Poschet,
  • Karsten Richter,
  • Nikolai Schleußner,
  • Rene-Filip Jackstadt,
  • Sonja Loges,
  • F. Nina Papavasiliou,
  • Xi Wang,
  • Jingxia Wu,
  • Guoliang Cui

摘要

Fatty acid (FA) oxidation plays an important role in T cell responses. However, whether DGAT1-mediated FA esterification to triacylglycerol also regulates T cell function remains unclear. Here we uncover a sexually dimorphic requirement for DGAT1 expression in CD8+ tumour-infiltrating lymphocyte function. In female mice, T cell-specific Dgat1 deficiency improves mitochondrial metabolic fitness and expands the pool of progenitor exhausted CD8+ T (Tex) cells to sustain antitumour responses. In male mice, however, Dgat1 deficiency leads to FA peroxidation, endoplasmic reticulum (ER) stress and CD8+ Tex cell death. We show that these effects are mediated by androgen receptor (AR) signalling. Deletion of Ar, overexpression of glutathione peroxidase 4, or inhibition of ER stress-induced cell death rescues Dgat1-deficient CD8+ T cell survival and promotes antitumour responses in male mice. Overall, this study suggests that DGAT1 detoxifies AR signalling in male mice to protect against ER stress-induced cell death and maintain T cell stemness, and uncovers sex-specific metabolic adaptations in the tumour microenvironment.