A phosphoglycerate mutase 1 allosteric inhibitor restrains TAM-mediated colon cancer progression

• DOI: 10.1016/j.apsb.2024.09.007
• Publication Date: 2024-09-14T06:44:40Z
• Authors: Cheng Wang; Minghao Zhang; Shunyao Li; Miaomiao Gong; Ming-yu Luo; Mo-cong Zhang; Jing-Hua Zou; Ningxiang Shen; Lu Xu; Hui-min Lei; Ling Bi; Liang Zhu; Zhengting Wang; Hong-zhuan Chen; Lu Zhou; Ying Shen

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.