Wang Cheng, Zhang Minghao, Li Shunyao, Gong Miaomiao, Luo Ming-Yu, Zhang Mo-Cong, Zou Jing-Hua, Shen Ningxiang, Xu Lu, Lei Hui-Min, Bi Ling, Zhu Liang, Wang Zhengting, Chen Hong-Zhuan, Zhou Lu, Shen Ying
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.
Collaborative Innovation Center for Clinical and Translational Science by Chinese Ministry of Education & Shanghai, Shanghai 200025, China.
Acta Pharm Sin B. 2024 Nov;14(11):4819-4831. doi: 10.1016/j.apsb.2024.09.007. Epub 2024 Sep 14.
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 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.
结直肠癌（CRC）是一种常见的恶性肿瘤，常导致肝转移和死亡。尽管PD-1/PD-L1免疫疗法取得了一些成功，但结肠癌患者的缓解率仍然相对较低。这与肿瘤相关巨噬细胞（TAM）介导的免疫抑制肿瘤微环境密切相关。我们之前的研究发现，磷酸甘油酸变位酶1（PGAM1）变构抑制剂HKB99在肺癌中具有一系列抗肿瘤活性。在这里，我们发现，在人类结肠癌样本中，尤其是在肝转移组织中， 的上调与M2样肿瘤相关巨噬细胞（TAM）水平的增加相关。HKB99在细胞培养和同基因肿瘤模型中抑制肿瘤生长和转移。HKB99逆转了由结肠癌细胞共培养诱导的M2极化。相反，HKB99显著抑制了M2-TAM诱导的结肠癌细胞迁移增加。值得注意的是，HKB99介导的抗肿瘤作用需要TAM浸润减少，同时CD8 T细胞浸润增加。此外，HKB99提高了同基因肿瘤中抗PD-1治疗的疗效。总体而言，本研究突出了HKB99在TAM介导的结肠癌进展中的抑制活性。靶向PGAM1可能会带来新的治疗策略，并提高现有结肠癌免疫疗法的有效性。
