Immune checkpoint blockade(ICB)therapy,which has revolutionized cancer treatment,has been approved for the treatment of triple-negative breast cancer(TNBC).Unfortunately,most patients with TNBC are either not eligible...Immune checkpoint blockade(ICB)therapy,which has revolutionized cancer treatment,has been approved for the treatment of triple-negative breast cancer(TNBC).Unfortunately,most patients with TNBC are either not eligible for treatment or exhibit resistance,resulting in limited overall survival benefits.There is an urgent need to elucidate the mechanisms of resistance and enhance therapeutic efficacy.Here,via CRISPR activation(CRISPRa)screening,we identified family with sequence similarity 114 member A1(FAM114A1)as a key mediator of immune evasion and ICB resistance in TNBC.Mechanistically,FAM114A1 binds p85αto disrupt the p85α/p110αprotein complex,thus activating the PI3K/AKT pathway and simultaneously preventing condensate formation of E2F Transcription Factor 4(E2F4)to promote E2F4-driven Metadherin(MTDH)transcription.Upregulation of these FAM114A1-mediated pathways suppresses tumor antigen presentation and consequently attenuates antitumor immunity in TNBC.Moreover,targeting FAM114A1 improves the therapeutic effectiveness of anti-PD-1 therapy in mouse models,and a FAM114A1-based signature shows strong predictive performance for identifying patients with TNBC who may benefit from ICB.Collectively,our findings not only reveal that FAM114A1 is an immune evasion driver but also highlight it as a promising biomarker and therapeutic target.Our study provides new insights into TNBC immune evasion and outlines a potential avenue to improve the effectiveness of ICB.展开更多
Dysregulation of lipid metabolism is a key characteristic of the tumor microenvironment,where tumor cells utilize lipids for proliferation,survival,metastasis,and evasion of immune surveillance.Lipid metabolism has be...Dysregulation of lipid metabolism is a key characteristic of the tumor microenvironment,where tumor cells utilize lipids for proliferation,survival,metastasis,and evasion of immune surveillance.Lipid metabolism has become a critical regulator of CD8+T-cell-mediated antitumor immunity,with excess lipids in the tumor microenvironment impeding CD8+T-cell activities.Considering the limited efficacy of immunotherapy in many solid tumors,targeting lipid metabolism to enhance CD8+T-cell effector functions could significantly improve immunotherapy outcomes.In this review,we examine recent findings on how lipid metabolic processes,including lipid uptake,synthesis,and oxidation,regulate CD8+T cells within tumors.We also assessed the impact of different lipids on CD8+T-cell-mediated antitumor immunity,with a particular focus on how lipid metabolism affects mitochondrial function in tumor-infiltrating CD8+T cells.Furthermore,as cancer is a systemic disease,we examined systemic factors linking lipid metabolism to CD8+T-cell effector function.Finally,we summarize current therapeutic approaches that target lipid metabolism to increase antitumor immunity and enhance immunotherapy.Understanding the molecular and functional interplay between lipid metabolism and CD8+T cells offers promising therapeutic opportunities for cancer treatment.展开更多
基金supported by grants from the National Natural Science Foundation of China(2021hwyq55 and 82472950 to M.Shen,32270745 to Y.Lu)the Natural Science Foundation of Shanghai(23ZR1466500 to Y.Lu)+1 种基金the Shanghai Municipal Health Commission(2022YQ067 to Y.Lu)supported by the Human Phenome Data Center of Fudan University。
文摘Immune checkpoint blockade(ICB)therapy,which has revolutionized cancer treatment,has been approved for the treatment of triple-negative breast cancer(TNBC).Unfortunately,most patients with TNBC are either not eligible for treatment or exhibit resistance,resulting in limited overall survival benefits.There is an urgent need to elucidate the mechanisms of resistance and enhance therapeutic efficacy.Here,via CRISPR activation(CRISPRa)screening,we identified family with sequence similarity 114 member A1(FAM114A1)as a key mediator of immune evasion and ICB resistance in TNBC.Mechanistically,FAM114A1 binds p85αto disrupt the p85α/p110αprotein complex,thus activating the PI3K/AKT pathway and simultaneously preventing condensate formation of E2F Transcription Factor 4(E2F4)to promote E2F4-driven Metadherin(MTDH)transcription.Upregulation of these FAM114A1-mediated pathways suppresses tumor antigen presentation and consequently attenuates antitumor immunity in TNBC.Moreover,targeting FAM114A1 improves the therapeutic effectiveness of anti-PD-1 therapy in mouse models,and a FAM114A1-based signature shows strong predictive performance for identifying patients with TNBC who may benefit from ICB.Collectively,our findings not only reveal that FAM114A1 is an immune evasion driver but also highlight it as a promising biomarker and therapeutic target.Our study provides new insights into TNBC immune evasion and outlines a potential avenue to improve the effectiveness of ICB.
基金supported by fellowships from NJCCR to YT(DCHS20PPC024)and ZC(COCR23PDF017)and grants from the Ludwig Foundation,Brewster Foundation,American Cancer Society,Breast Cancer Research Foundation and Susan G.Komen Foundation to YK.All figures were made in BioRender.
文摘Dysregulation of lipid metabolism is a key characteristic of the tumor microenvironment,where tumor cells utilize lipids for proliferation,survival,metastasis,and evasion of immune surveillance.Lipid metabolism has become a critical regulator of CD8+T-cell-mediated antitumor immunity,with excess lipids in the tumor microenvironment impeding CD8+T-cell activities.Considering the limited efficacy of immunotherapy in many solid tumors,targeting lipid metabolism to enhance CD8+T-cell effector functions could significantly improve immunotherapy outcomes.In this review,we examine recent findings on how lipid metabolic processes,including lipid uptake,synthesis,and oxidation,regulate CD8+T cells within tumors.We also assessed the impact of different lipids on CD8+T-cell-mediated antitumor immunity,with a particular focus on how lipid metabolism affects mitochondrial function in tumor-infiltrating CD8+T cells.Furthermore,as cancer is a systemic disease,we examined systemic factors linking lipid metabolism to CD8+T-cell effector function.Finally,we summarize current therapeutic approaches that target lipid metabolism to increase antitumor immunity and enhance immunotherapy.Understanding the molecular and functional interplay between lipid metabolism and CD8+T cells offers promising therapeutic opportunities for cancer treatment.
