DGAT1 介导性别特异性 CD8(+) T 细胞抗肿瘤反应

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 (T ex ) cells to sustain antitumour responses. In male mice, however, Dgat1 deficiency leads to FA peroxidation, endoplasmic reticulum (ER) stress and CD8 + T ex 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.