Tumor extracellular vesicle–derived PD-L1 promotes T cell senescence through lipid metabolism reprogramming

• DOI: 10.1126/scitranslmed.adm7269
• Publication Date: 2025-02-12T18:59:31Z
• Authors: Feiya Ma; Xia Liu; Yuanqin Zhang; Yan Tao; Lei Zhao; Hazar Abusalamah; Cody Huffman; R. Alex Harbison; Sidharth V. Puram; Yuqi Wang; Guangyong Peng
• Keywords: Senescence; Adoptive Cell Transfer; Cancer Immunotherapy

The limited success of cancer immunotherapy has posed challenges in treating patients with cancer. However, promising strides could be made a deeper understanding the factors that cause T cell dysfunction within tumor microenvironment and by developing effective strategies to counteract tumor-induced immune suppression. Here, we report tumor-derived extracellular vesicles (tEVs) can induce senescence suppression cells. Programmed death ligand 1 (PD-L1), key component tEVs, induced DNA damage hyperactive lipid metabolism both human mouse This caused an elevated expression metabolic enzymes increase cholesterol droplet formation, leading cellular senescence. At molecular level, PD-L1 derived from tEVs activated cAMP-response element binding protein (CREB) signal transducer activator transcription (STAT) signaling, which promoted facilitated Inhibiting EV synthesis tumors or blocking CREB synthesis, formation effector cells averted tEV-mediated vitro vivo adoptive transfer melanoma models. same treatments also bolstered antitumor efficacy therapy anti–PD-L1 checkpoint These studies identified mechanistic links between tumor-mediated potential resistance, they provide new for immunotherapy.