A phosphoglycerate mutase 1 allosteric inhibitor restrains TAM-mediated colon cancer progression.
10.1016/j.apsb.2024.09.007
- Author:
Cheng WANG
1
;
Minghao ZHANG
1
;
Shunyao LI
2
;
Miaomiao GONG
1
;
Ming-Yu LUO
1
;
Mo-Cong ZHANG
1
;
Jing-Hua ZOU
1
;
Ningxiang SHEN
1
;
Lu XU
1
;
Hui-Min LEI
1
;
Ling BI
3
;
Liang ZHU
1
;
Zhengting WANG
4
;
Hong-Zhuan CHEN
5
;
Lu ZHOU
2
;
Ying SHEN
1
Author Information
1. Department of Pharmacology and Chemical Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
2. Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
3. Department of Medical Oncology & Cancer Institute of Integrative Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
4. Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
5. Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
- Publication Type:Journal Article
- Keywords:
Allosteric inhibitor;
Anti-PD-1;
Colon cancer;
Immunotherapy;
Liver metastasis;
Macrophage polarization;
Phosphoglycerate mutase 1;
Tumor-associated macrophages
- From:
Acta Pharmaceutica Sinica B
2024;14(11):4819-4831
- CountryChina
- Language:English
-
Abstract:
Colorectal cancer (CRC) is a prevalent malignant tumor often leading to liver metastasis and mortality. Despite some success with PD-1/PD-L1 immunotherapy, the response rate for colon cancer patients remains relatively low. This is closely related to the immunosuppressive tumor microenvironment mediated by tumor-associated macrophages (TAMs). Our previous work identified that a phosphoglycerate mutase 1 (PGAM1) allosteric inhibitor, HKB99, exerts a range of anti-tumor activities in lung cancer. Here, we found that upregulation of PGAM1 correlates with increased levels of M2-like tumor-associated macrophages (TAMs) in human colon cancer samples, particularly in liver metastatic tissues. HKB99 suppressed tumor growth and metastasis in cell culture and syngeneic tumor models. M2-polarization, induced by colon cancer cell co-culture, was reversed by HKB99. Conversely, the increased migration of colon cancer cells by M2-TAMs was remarkably restrained by HKB99. Notably, a decrease in TAM infiltration was required for the HKB99-mediated anti-tumor effect, along with an increase in CD8+ T cell infiltration. Moreover, HKB99 improved the efficacy of anti-PD-1 treatment in syngeneic tumors. Overall, this study highlights HKB99's inhibitory activity in TAM-mediated colon cancer progression. Targeting PGAM1 could lead to novel therapeutic strategies and enhance the effectiveness of existing immunotherapies for colon cancer.
