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Abstract Background: Pancreatic cancer, often resistant due to its immunologically "cold" nature and tumor-associated macrophages (TAMs), presents challenges in chemotherapy and immunotherapy. This study uses single-cell transcriptomics to assess TAM subsets in response to surufatinib, an inhibitor targeting CSF-1R, FGFR1, and VEGFR1-3. Methods: Surufatinib-treated patient samples were analyzed using single-cell RNA sequencing to identify altered macrophage subsets. Additional techniques, such as flow cytometry, tissue microarrays, co-culture assays, and macrophage-specific knockout mice, were used for further study. Western blot and immunofluorescence clarified the molecular functions of TAMs, and the impact of targeting these TAMs on PD-1 therapy was evaluated in a pancreatic cancer mouse model. Results: Single-cell RNA sequencing revealed macrophage subsets with increased GPR34 expression following surufatinib treatment. The Gpr34fl/flLYZ2Cre mouse orthotopic-transplanted tumor model, treated with gemcitabine and albumin-bound paclitaxel, showed significantly reduced tumor growth compared to the control group, with notably lower percentages of exhausted T (Tex) cells and regulatory T (Treg) cells, and a significant increase in cytotoxic T cells in tumor tissue. LysoPS, produced by chronically injured pancreatic cancer cells, promotes the differentiation of bone marrow-derived monocytes (BMDM) into an immunosuppressive phenotype, an effect abolished after siGpr34 transfection. The LysoPS-GPR34 axis can significantly activate the NF-κB signaling pathway in BMDMs, potentially inducing the senescence-related secretory phenotype (SASP) and contributing to the macrophages' immunosuppressive phenotype. Combining a GPR34 antagonist with αPD-1 and PD-L1 inhibitors significantly curbed tumor growth and enhanced the immune environment in KPC mice. Conclusions: Elevated GPR34 in TAMs enhances immunosuppression via the NF-κB pathway, affecting T cell distribution. GPR34's role could be key in optimizing surufatinib treatment for pancreatic cancer, indicating new therapeutic avenues. Citation Format: Xiaofan Guo, Yuxiao Liu, Yuning Song, Jing Huang, Wenbo Zhu, Peijun Xu, Jun Yu, Song Gao, Jihui Hao. Surufatinib treatment in pancreatic cancer: unveiling the role of GPR34 in TAMs and enhancing immunotherapy efficacy abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 2128.
Guo et al. (Fri,) studied this question.