The gut microbiota crucially regulates the efficacy of immune checkpoint inhibitor(ICl)based immunotherapy,but the underlying mechanisms remain unclear at the single-cell resolution.Using single-cell RNA sequencing an...The gut microbiota crucially regulates the efficacy of immune checkpoint inhibitor(ICl)based immunotherapy,but the underlying mechanisms remain unclear at the single-cell resolution.Using single-cell RNA sequencing and subsequent validations,we investigate gut microbiota-ICl synergy by profling the tumor microenvironment(TME)and elucidating critical cellular interactions in mouse models.Our findings reveal that intact gut microbiota combined with ICls may synergistically increase the proportions of CD8^(+),CD4^(+),and yδ T cells,reduce glycolysis metabolism,and reverse exhausted CD8^(+)T cells into memory/effector CD8^(+)T cells,enhancing antitumor response.This synergistic effect also induces macrophage reprogramming from M2 protumor Spp1^(+)tumorassociated macrophages(TAMs)to Cd74^(+)TAMs,which act as antigen-presenting cells(APCs).These macrophage subtypes show a negative correlation within tumors,particularly during fecal microbiota transplantation.Depleting Spp1^(+)TAMs in Spp1 conditional knockout mice boosts ICl efficacy and T cell infiltration,regardless of gut microbiota status,suggesting a potential upstream role of the gut microbiota and highlighting the crucial negative impact of Spp1^(+)TAMs during macrophage reprogramming on immunotherapy outcomes.Mechanistically,we propose aγδT cell-APC-CD8^(+)T cell axis,where gut microbiota and ICls enhance Cd40lg expression onγδT cells,activating Cd40 overexpressing APCs(e.g.,Cd74^(+)TAMs)through CD40-CD40L-related NF-kB signaling and boosting CD8^(+)T cell responses via CD86-CD28 interactions.These findings highlight the potential importance of y8 T cells and SPP1-related macrophage reprogramming in activating CD8^(+)T cells,as well as the synergistic effect of gut microbiota and ICls in immunotherapy through modulating the TME.展开更多
基金supported by the National Key R&D Program of China(No.2021YFA1301200,and 2023YFC3405200)National Natural Science Foundation of China(No.82273445)+4 种基金Sichuan Science and Technology Program(No.2025ZNSFSC0046)Sichuan Provincial Youth Foundation(No.2025ZNSFSC1903)China Postdoctoral Science Foundation(No.2024M762235)Postdoctor Research Fund of West China Hospital,Sichuan University(2024HXBH033)1.3.5 Project for Disciplines of Excellence from West China Hospital of Sichuan University(No.ZYYC23025,ZYYC23013).
文摘The gut microbiota crucially regulates the efficacy of immune checkpoint inhibitor(ICl)based immunotherapy,but the underlying mechanisms remain unclear at the single-cell resolution.Using single-cell RNA sequencing and subsequent validations,we investigate gut microbiota-ICl synergy by profling the tumor microenvironment(TME)and elucidating critical cellular interactions in mouse models.Our findings reveal that intact gut microbiota combined with ICls may synergistically increase the proportions of CD8^(+),CD4^(+),and yδ T cells,reduce glycolysis metabolism,and reverse exhausted CD8^(+)T cells into memory/effector CD8^(+)T cells,enhancing antitumor response.This synergistic effect also induces macrophage reprogramming from M2 protumor Spp1^(+)tumorassociated macrophages(TAMs)to Cd74^(+)TAMs,which act as antigen-presenting cells(APCs).These macrophage subtypes show a negative correlation within tumors,particularly during fecal microbiota transplantation.Depleting Spp1^(+)TAMs in Spp1 conditional knockout mice boosts ICl efficacy and T cell infiltration,regardless of gut microbiota status,suggesting a potential upstream role of the gut microbiota and highlighting the crucial negative impact of Spp1^(+)TAMs during macrophage reprogramming on immunotherapy outcomes.Mechanistically,we propose aγδT cell-APC-CD8^(+)T cell axis,where gut microbiota and ICls enhance Cd40lg expression onγδT cells,activating Cd40 overexpressing APCs(e.g.,Cd74^(+)TAMs)through CD40-CD40L-related NF-kB signaling and boosting CD8^(+)T cell responses via CD86-CD28 interactions.These findings highlight the potential importance of y8 T cells and SPP1-related macrophage reprogramming in activating CD8^(+)T cells,as well as the synergistic effect of gut microbiota and ICls in immunotherapy through modulating the TME.
