The lactate receptor HCAR1 drives the recruitment of immunosuppressive PMN-MDSCs in colorectal cancer

Jiacheng He , Xiaolei Chai, Qiansen Zhan , Yang Wang, Yijie Wang, Xinyu Yang, Jingbo Wu, Bo Feng, Jing Sun, Weiwei Rui, Shuyin Ze, Yuanyuan Fu, Yumiao Zhao, Ying Zhang, Yao Zhang, Meizhen Liu, Chuang Liu, Meifu She, Xiangfei Hu, Xueyun Ma,  Huaiyu Yang, Dawei Li , Senlin Zhao, Guichao Li, Zhen Zhang, Zhonghui Tian, Yanlin Ma, Lingyan Cao, Bo Yi, Dali Li, Ruth Nussinov , Charis Eng, Timothy A. Chan Eytan Ruppin, J. Silvio Gutkind, Feixiong Cheng , Mingyao Liu & Weiqiang Lu

Nature Immunology | Volume 26 | 2025 |391-403

Most patients with colorectal cancer do not achieve durable clinical benefits from immunotherapy, underscoring the existence of alternative immunosuppressive mechanisms. Here we found that activation of the lactate receptor HCAR1 signaling pathway induced the expression of chemokines CCL2 and CCL7 in colorectal tumor cells, leading to the recruitment of immunosuppressive CCR2+ polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) to the tumor microenvironment. Ablation of Hcar1 in mice with colorectal tumors significantly decreased the abundance of tumor-infiltrating CCR2+ PMN-MDSCs, enhanced the activation of CD8+ T cells and, consequently, reduced tumor burden. We detected immunosuppressive CCR2+ PMN-MDSCs in tumor specimens from individuals with colorectal and other cancers. The US Food and Drug Administration-approved drug reserpine suppressed lactate-mediated HCAR1 activation, impaired the recruitment of CCR2+ PMN-MDSCs, boosted CD8+ T cell-dependent antitumor immunity and sensitized immunotherapy-resistant tumors to programmed cell death protein 1 antibody therapy in mice with colorectal tumors. Altogether, we described HCAR1-driven recruitment of CCR2+ PMN-MDSCs as a mechanism of immunosuppression.