1.A phosphoglycerate mutase 1 allosteric inhibitor restrains TAM-mediated colon cancer progression.
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
Acta Pharmaceutica Sinica B 2024;14(11):4819-4831
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.
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