Inhibition of CCT5-mediated asparagine biosynthesis and anti-PD-L1 produce synergistic antitumor effects in colorectal cancer.
10.1016/j.apsb.2025.03.026
- Author:
Yujie ZHANG
1
;
Weiyi ZHAO
1
;
Ling WU
1
;
Tianjing AI
2
;
Jie HE
2
;
Zetao CHEN
3
;
Chuangyuan WANG
3
;
Hui WANG
4
;
Rui ZHOU
2
;
Chaoqun LIU
1
;
Liang ZHAO
1
Author Information
1. Department of Pathology, Nanfang Hospital, Southern Medical University Guangzhou 510515, China.
2. Department of Pathology & Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
3. Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510260, China.
4. Department of Medical Oncology, Affiliated Tumour Hospital of Guangzhou Medical University, Guangzhou 510095, China.
- Publication Type:Journal Article
- Keywords:
ASNS;
ASNase;
Anti-PD-L1 immunotherapy;
Asparagine metabolism;
CCT5;
CD8+ T cell;
Colorectal cancer;
Combination therapy
- From:
Acta Pharmaceutica Sinica B
2025;15(5):2480-2497
- CountryChina
- Language:English
-
Abstract:
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.
