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<p>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 <i>GPR34</i> expression. In <i>Gpr34</i><sup>Δ<i>Lyz2</i></sup> mouse models and in vitro co-cultures, GPR34<sup>+</sup> 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<sup>+</sup> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月28日

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  • 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

摘要

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.