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

  • Signal Transduct Target Ther. 2026 Apr 28;11(1):156. doi: 10.1038/s41392-026-02641-4.
Xiaofan Guo  #  1 ,  Yuxiao Liu  #  2 ,  Tianchen Li  #  1 ,  Xiaopeng An  #  1 ,  Yuning Song  1 ,  Peijun Xu  1 ,  Jing Huang  1 ,  Yiping Zou  1 ,  Bohang Xu  1 ,  Yongjie Xie  1 ,  Zekun Li  1 ,  Chenyang Meng  1 ,  Tiansuo Zhao  1 ,  Xiuchao Wang  1 ,  Hongwei Wang  1 ,  Chuntao Gao  1 ,  Xuan Zhou  3 ,  Jun Yu  4 ,  Song Gao  5 ,  Jihui Hao  6
Affiliations
  • 1. Pancreas Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, State Key Laboratory of Draggability Evaluation and Systematic Translational Medicine, Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China.
  • 2. The First Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China.
  • 3. Department of Maxillofacial and Otorhinolaryngology Oncology, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin Cancer Institute, National Clinical Research Center of Cancer, Tianjin, China.
  • 4. Pancreas Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, State Key Laboratory of Draggability Evaluation and Systematic Translational Medicine, Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China. [email protected].
  • 5. Pancreas Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, State Key Laboratory of Draggability Evaluation and Systematic Translational Medicine, Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China. [email protected].
  • 6. Pancreas Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, State Key Laboratory of Draggability Evaluation and Systematic Translational Medicine, Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China. [email protected].
  • # Contributed equally.
PMID: 42045172 DOI: 10.1038/s41392-026-02641-4
Abstract

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.

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