biostudies-literatureSimula LAssociazione Italiana per la Ricerca sul CancroFondazione Italiana Sclerosi Multipla188-205https://www.ebi.ac.uk/biostudies/studies/S-EPMC8732338biostudies-literatureUnknown16(1)Programmed cell death-1 (PD-1) signaling downregulates the T-cell response, promoting an exhausted state in tumor-infiltrating T cells, through mostly unveiled molecular mechanisms. Dynamin-related protein-1 (Drp1)-dependent mitochondrial fission plays a crucial role in sustaining T-cell motility, proliferation, survival, and glycolytic engagement. Interestingly, such processes are exactly those inhibited by PD-1 in tumor-infiltrating T cells. Here, we show that PD-1^pos CD8⁺ T cells infiltrating an MC38 (murine adenocarcinoma)-derived murine tumor mass have a downregulated Drp1 activity and more elongated mitochondria compared with PD-1^neg counterparts. Also, PD-1^pos lymphocytic elements infiltrating a human colon cancer rarely express active DrpMolecular oncologyPD-1-induced T cell exhaustion is controlled by a Drp1-dependent mechanism.PMC87323382018/S/5IG‐2017 198262016/R/18Campello SScarpelli GColamatteo ACancila VDe Angelis BAntonucci YQuintarelli CMatarese GTripodo CSimula LProcaccini CManni SfalsePD-1-induced T cell exhaustion is controlled by a Drp1-dependent mechanism.Programmed cell death-1 (PD-1) signaling downregulates the T-cell response, promoting an exhausted state in tumor-infiltrating T cells, through mostly unveiled molecular mechanisms. Dynamin-related protein-1 (Drp1)-dependent mitochondrial fission plays a crucial role in sustaining T-cell motility, proliferation, survival, and glycolytic engagement. Interestingly, such processes are exactly those inhibited by PD-1 in tumor-infiltrating T cells. Here, we show that PD-1^pos CD8⁺ T cells infiltrating an MC38 (murine adenocarcinoma)-derived murine tumor mass have a downregulated Drp1 activity and more elongated mitochondria compared with PD-1^neg counterparts. Also, PD-1^pos lymphocytic elements infiltrating a human colon cancer rarely express active Drp2022-01-01T00:00:00Z2022 Jan2025-04-18T17:09:31.385Z2022-02-11T15:08:22.969ZS-EPMC87323383453594910.1002/1878-0261.13103