2. Academic Validation
  3. Tumor-derived CCL5 recruits CCR1+ macrophages to suppress apoptosis and drive proliferation in duodenal adenocarcinoma

Tumor-derived CCL5 recruits CCR1+ macrophages to suppress apoptosis and drive proliferation in duodenal adenocarcinoma

  • Cancer Lett. 2025 Sep 25:634:218064. doi: 10.1016/j.canlet.2025.218064.
Jiaoduan Li 1,  Liyi Zhang 2,  Chen Zheng 3,  Xiaolin Lin 4,  Dongyan Cao 3,  Shasha Zhao 3,  Shuang Wang 3,  Bin Yu 3,  Guiying Wei 5,  Xianming Kong 6,  Xiao Liu 7,  Aina He 8,  Xiuying Xiao 9,  Dongxi Xiang 10
Affiliations

Affiliations

  • 1 State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Department of Biliary-Pancreatic Surgery, Department of Gastrointestinal Surgery, Shanghai Key Laboratory of Cancer System Regulation and Clinical Translation, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; Department of Dermatology, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, PR China.
  • 2 Department of Breast Surgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, PR China.
  • 3 State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Department of Biliary-Pancreatic Surgery, Department of Gastrointestinal Surgery, Shanghai Key Laboratory of Cancer System Regulation and Clinical Translation, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
  • 4 Department of Oncology, The Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, PR China.
  • 5 Shanghai OneTar Biomedicine, Shanghai, PR China.
  • 6 Shanghai Institute of Health Sciences, Shanghai, PR China.
  • 7 State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Department of Biliary-Pancreatic Surgery, Department of Gastrointestinal Surgery, Shanghai Key Laboratory of Cancer System Regulation and Clinical Translation, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China. Electronic address: lxc417@sjtu.edu.cn.
  • 8 Department of Oncology, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, PR China. Electronic address: ai_na_he@yahoo.com.
  • 9 Department of Oncology, The Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, PR China. Electronic address: xiaoxiuying2002@163.com.
  • 10 State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Department of Biliary-Pancreatic Surgery, Department of Gastrointestinal Surgery, Shanghai Key Laboratory of Cancer System Regulation and Clinical Translation, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor (Guangxi Medical University), Ministry of Education, Nanning, PR China; Jiaxing Organoid Center, Jiaxing, Zhejiang, PR China. Electronic address: dxiang@shsmu.edu.cn.
PMID: 41015267 DOI: 10.1016/j.canlet.2025.218064
Abstract

Duodenal adenocarcinoma (DA) is a rare gastrointestinal malignancy associated with poor prognosis and limited therapeutic options. To define the DA tumor microenvironment (TME), we performed single-cell RNA Sequencing (scRNA-seq) on primary DA tumors and matched adjacent normal tissues. This analysis revealed substantial heterogeneity among malignant epithelial cells, including a transcriptionally distinct subset characterized by the upregulation of immune-related genes, which constitutes an immune-associated transcriptional program. Notably, this program included high expression of the chemokine CCL5, which facilitated the recruitment of CCR1+ macrophages. Using patient-derived DA organoids, we identified malignant cells exhibiting immune-related transcriptional signatures, including elevated CCL5. Functional assays demonstrated that CCL5 promoted CCR1+ macrophage migration, an effect suppressed by both the CCR1 Antagonist BX471 and CCL5-neutralizing antibody. In co-culture, CCL5-expressing DA organoids displayed enhanced survival and proliferation in the presence of CCR1+ macrophages, while pharmacological blockade of CCR1 significantly increased tumor cell death. Bulk transcriptomic profiling revealed that CCR1 downregulates pro-apoptotic signaling in tumor cells, thereby promoting cell survival and growth. Importantly, combining CCL5/CCR1 inhibitors with standard chemotherapeutic agents resulted in synergistic tumor cell killing. Together, our findings establish the CCL5/CCR1 axis as a key mediator of tumor-macrophage crosstalk in DA, supporting immune evasion and chemoresistance via suppression of macrophage-induced Apoptosis. Targeting this axis may represent a promising therapeutic strategy to enhance the efficacy of conventional chemotherapy in DA.

Keywords

CCL5; CCR1; Duodenal adenocarcinoma; Macrophage; Organoid.

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