Targeting GPR34 in damage-associated macrophages enhances anti-tumor immunity and the efficacy of Surufatinib in pancreatic cancer

Xiaofan, Guo, Yuxiao, Liu, Tianchen, Li, Xiaopeng, An, Yuning, Song, Peijun, Xu, Jing, Huang, Yiping, Zou, Bohang, Xu, Yongjie, Xie, Zekun, Li, Chenyang, Meng, Tiansuo, Zhao, Xiuchao, Wang, Hongwei, Wang, Chuntao, Gao, Xuan, Zhou, Jun, Yu, Song, Gao, Jihui, Hao

Signal Transduction and Targeted Therapy |

Tumor-associated macrophages (TAMs) are pivotal in the immunosuppressive tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC). The efficacy of targeting the CSF-1/CSF-1R axis in PDAC remains uncertain. Using single-cell RNA sequencing on specimens from patients treated with Surufatinib plus chemotherapy, we identified a distinct subset of damage-associated macrophages (DAMs) characterized by high GPR34 expression. In Gpr34ΔLyz2 mouse models and in vitro co-cultures, GPR34+ macrophages responded to tissue damage by releasing lysophosphatidylserine (LysoPS), which enhanced CXCL16 secretion and efferocytosis. This efferocytosis promoted MHC-I degradation via the macrophage lysosomal pathway, leading to CD8+ T cell exhaustion. Combining a GPR34 antagonist with chemotherapy and surufatinib significantly enhanced anti-tumor responses in preclinical models. These findings identify GPR34 as a promising immune therapeutic target.