CD8+T cells within the tumor microenvironment(TME)are often functionally impaired,which limits their ability to mount effective anti-tumor responses.However,the molecular mechanisms behind this dysfunction remain inco...CD8+T cells within the tumor microenvironment(TME)are often functionally impaired,which limits their ability to mount effective anti-tumor responses.However,the molecular mechanisms behind this dysfunction remain incompletely understood.Here,we identified valosin-containing protein(VCP)as a key regulator of CD8+T cells suppression in hepatocellular carcinoma(HCC).Our findings reveal that VCP suppresses the activation,expansion,and cytotoxic capacity of CD8+T cells both in vitro and in vivo,significantly contributing to the immunosuppressive nature of the TME.Mechanistically,VCP stabilizes the expression of glycerol-3-phosphate dehydrogenase 1-like protein(GPD1L),leading to the accumulation of glycerol-3-phosphate(G3P),a downstream metabolite of GPD1L.The accumulated G3P diffuses into the TME and directly interacts with SRC-family tyrosine kinase LCK,a critical component of the T-cell receptor(TCR)signaling pathway in CD8+T cells.This interaction heightens the phosphorylation of Tyr505,a key inhibitory residue,ultimately reducing LCK activity and impairing downstream TCR signaling.Consequently,CD8+T cells lose their functional capacity,diminishing their ability to fight against HCC.Importantly,we demonstrated that targeting VCP in combination with anti-PD1 therapy significantly suppresses HCC tumor growth and restores the anti-tumor function of CD8+T cells,suggesting synergistic therapeutic potential.These findings highlight a previously unrecognized mechanism involving VCP and G3P in suppressing T-cell-mediated immunity in the TME,positioning VCP as a promising upstream target for enhancing immunotherapy in HCC.展开更多
基金supported by the following source.National Key R&D Program of China(Grant No.2019YFA0709300)Noncommunicable Chronic Diseases-National Science and Technology Major Project(Grant No.2023ZD0507500)+7 种基金National Natural Science Foundation of China(Grant Nos.U19A2008,81972307,82102705,82272787,82373232,and 82473189)Natural Science Foundation of Anhui Province(2208085J47,2408085QH255)Provincial Key R&D Program of Anhui Province(202204295107020025,202204295107020022)The Strategic Priority Research Program of the Chinese Academy of Sciences(Grant No.XDB0940201)Scientific Research Project of Anhui Provincial Department of Education(Grant No.2022AH030125)Beijing Xisike Clinical Oncology Research Foundation(Grant No.Y-JS2019-014).Research Funds of Centre for Leading Medicine and Advanced Technologies of IHM(Grant No.2023IHM01031)USTC Research Funds of the Double First-Class Initiative(YD9110002048,YD9110002050,and YD9110002068)Program for Innovative Research Team of The First Affiliated Hospital of USTC(CXGG01).
文摘CD8+T cells within the tumor microenvironment(TME)are often functionally impaired,which limits their ability to mount effective anti-tumor responses.However,the molecular mechanisms behind this dysfunction remain incompletely understood.Here,we identified valosin-containing protein(VCP)as a key regulator of CD8+T cells suppression in hepatocellular carcinoma(HCC).Our findings reveal that VCP suppresses the activation,expansion,and cytotoxic capacity of CD8+T cells both in vitro and in vivo,significantly contributing to the immunosuppressive nature of the TME.Mechanistically,VCP stabilizes the expression of glycerol-3-phosphate dehydrogenase 1-like protein(GPD1L),leading to the accumulation of glycerol-3-phosphate(G3P),a downstream metabolite of GPD1L.The accumulated G3P diffuses into the TME and directly interacts with SRC-family tyrosine kinase LCK,a critical component of the T-cell receptor(TCR)signaling pathway in CD8+T cells.This interaction heightens the phosphorylation of Tyr505,a key inhibitory residue,ultimately reducing LCK activity and impairing downstream TCR signaling.Consequently,CD8+T cells lose their functional capacity,diminishing their ability to fight against HCC.Importantly,we demonstrated that targeting VCP in combination with anti-PD1 therapy significantly suppresses HCC tumor growth and restores the anti-tumor function of CD8+T cells,suggesting synergistic therapeutic potential.These findings highlight a previously unrecognized mechanism involving VCP and G3P in suppressing T-cell-mediated immunity in the TME,positioning VCP as a promising upstream target for enhancing immunotherapy in HCC.
