Abnormal amino acid metabolism promotes tumor progression by inducing malignant behaviors in tumor cells and altering the immune landscape within the tumor microenvironment.However,the underlying mechanisms remain unc...Abnormal amino acid metabolism promotes tumor progression by inducing malignant behaviors in tumor cells and altering the immune landscape within the tumor microenvironment.However,the underlying mechanisms remain unclear.In this study,we constructed colorectal cancer(CRC)organoids and patient-derived tumor xenograft(PDX)models,performing multifaceted validation to confirm that T-complex protein 1 subunit epsilon(CCT5),mediates the biosynthesis of aspartate and enhances sensitivity to anti-PD-L1 immunotherapy.Mechanistically,CCT5 directly binds to asparagine synthetase(ASNS)and promotes the synthesis of aspartate(Asn).The Asn–mTORC1 axis facilitates tumor cell proliferation while upregulating PD-L1 expression,which leads to a reduction in the number of effector CD8+T cells.Treatment with l-asparaginase(ASNase)combined with anti-PD-L1 therapy effectively reverses the growth of CRC characterized by high CCT5 expression.In summary,we identify CCT5 as a potential biomarker to guide the combined use of ASNase and anti-PD-L1 antibodies in CRC treatment.展开更多
基金Noncommunicable Chronic Diseases-National Science and Technology Major Project(2023ZD0500103,China)National Natural Science Foundation of China(82472895 and 82173172)+1 种基金Guangzhou Basic and Applied Basic Research Foundation(2024A04J6605,China)China Postdoctoral Science Foundation(2022M721540 and 2023M741569,China).
文摘Abnormal amino acid metabolism promotes tumor progression by inducing malignant behaviors in tumor cells and altering the immune landscape within the tumor microenvironment.However,the underlying mechanisms remain unclear.In this study,we constructed colorectal cancer(CRC)organoids and patient-derived tumor xenograft(PDX)models,performing multifaceted validation to confirm that T-complex protein 1 subunit epsilon(CCT5),mediates the biosynthesis of aspartate and enhances sensitivity to anti-PD-L1 immunotherapy.Mechanistically,CCT5 directly binds to asparagine synthetase(ASNS)and promotes the synthesis of aspartate(Asn).The Asn–mTORC1 axis facilitates tumor cell proliferation while upregulating PD-L1 expression,which leads to a reduction in the number of effector CD8+T cells.Treatment with l-asparaginase(ASNase)combined with anti-PD-L1 therapy effectively reverses the growth of CRC characterized by high CCT5 expression.In summary,we identify CCT5 as a potential biomarker to guide the combined use of ASNase and anti-PD-L1 antibodies in CRC treatment.
