Abstract 6818: GPR34-driven damage-response macrophages underlie therapeutic resistance to surufatinib
Authors: Xiaofan Guo, Yuxiao Liu, Yiping Zou, Wenbo Zhu, Peijun Xu, Yuning Song, Jing Huang, Xiaopeng An, Song Gao, Jihui Hao
Journal: Cancer Research (2025)

Abstract Background: Pancreatic cancer, an immunologically "cold" tumor, poorly responds to immunotherapy. TAMs, key immune cells in its microenvironment, drive tumor progression. Despite recent progress in macrophage-targeted therapies like CSF1R inhibitors, clinical results in pancreatic cancer are disappointing, with unclear mechanisms. Surufatinib, a CSF1R inhibitor, hinders macrophage differentiation into an immunosuppressive state. Surufatinib alters macrophage differentiation pathways, but resistance is mediated by the emergence of damage-associated macrophages. A subset of these macrophages, characterized by high GPR34 expression, is enriched in refractory pancreatic cancer patients. Through activation of the LysoPS-GPR34 axis, these macrophages enhance efferocytosis and subsequently downregulate MHC-I, leading to CD8+ T cell exhaustion. Method: Tumor immune microenvironment alterations in pancreatic cancer patients after surufatinib treatment were analyzed via scRNA-seq. Multiplex immunofluorescence staining and flow cytometry were performed on tumor tissue microarrays and fresh surgical specimens. GPR34 conditional knockout mice with orthotopic tumors were analyzed via flow cytometry. The mechanisms of CD8+ T cell exhaustion were investigated using in vitro co-culture systems of macrophages and CD8+ T cells. The efficacy of GPR34 antagonists in combination with immunotherapy and chemotherapy was evaluated in spontaneous tumor models. Result: Single-cell RNA sequencing (scRNA-seq) was performed on tumor specimens from patients enrolled in clinical trials receiving surufatinib plus chemotherapy. The analysis revealed changes in the tumor immune microenvironment, identifying a subset of damage-response macrophages characterized by high GPR34 expression. Notably, this macrophage population was significantly enriched in treatment-resistant patients. These high expression GPR34 macrophages activated damage-response signaling via the lysophosphatidylserine (LysoPS)-GPR34 axis, promoting CD8+ T cell exhaustion through the release of chronic inflammatory factors and enhanced efferocytosis. Furthermore, efferocytosis further promotes the formation of autophagolysosomes in macrophages, leading to increased degradation of MHC-I, thereby suppressing the antigen-presenting function of macrophages. Targeting GPR34+ macrophages significantly improved the efficacy of both immunotherapy and chemotherapy. Conclusion: Surufatinib alters macrophage differentiation pathways, but resistance is mediated by the emergence of damage-associated macrophages. A subset of these macrophages, characterized by high GPR34 expression, is enriched in refractory pancreatic cancer patients. Through activation of the LysoPS-GPR34 axis, these macrophages enhance efferocytosis and subsequently downregulate MHC-I, leading to CD8+ T cell exhaustion. Citation Format: Xiaofan Guo, Yuxiao Liu, Yiping Zou, Wenbo Zhu, Peijun Xu, Yuning Song, Jing Huang, Xiaopeng An, Song Gao, Jihui Hao. GPR34-driven damage-response macrophages underlie therapeutic resistance to surufatinib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6818.