{
  "abstract": "Background Immune checkpoint inhibitors (ICIs) have been proven to be one of the most promising and effective immunotherapies; however, their efficacy in colorectal cancer (CRC) remains significantly limited. Therefore, understanding the mechanism of resistance to ICIs therapy in CRC patients is of great significance for the development of new anti-tumor immunotherapy targets.Methods Ccl7 myeloid cell-specific knockout mice and MC38 tumor-bearing mouse models were established to investigate the role of Ccl7 during CRC progression. Proteomic analysis, RNA-seq, and flow cytometry analysis were used to determine the role of Ccl7 in the tumor immune microenvironment.Results Herein, we found that elevated CCL7 + tumor-associated macrophages (TAMs) in tumors correlated with tolerance to ICIs blockage therapy in patients with CRC. Deletion of CCL7 in myeloid cells resulted in reduced accumulation of immunosuppressive TAMs and increased infiltration of activated CD8+ T cells within the tumor. Mechanistically, CCL7 modulates peroxisome biogenesis and fatty acid oxidation, thereby promoting the immunosuppressive functions of TAMs via the PI3K-AKT-PEX3 signaling pathway. Furthermore, CCL7 inhibits the expression of chemokine CXCL10 by suppressing the AKT2-STAT1 signaling pathway, which reduces the infiltration of activated CD8+ T cells in the tumor. Blocking CCL7 delays CRC progression and enhances the therapeutic efficacy of PD-L1.Conclusion Our study highlights the novel role and regulatory mechanisms of CCL7 + TAMs in ICIs immunotherapy resistance, suggesting that CCL7 may serve as a potential combined therapeutic target for ICIs immunotherapy.",
  "authors": [
    {
      "affiliations": [
        "School of Medicine, Chongqing University Cancer Hospital, Chongqing University, Chongqing, People's Republic of China",
        "Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, China"
      ],
      "name": "Yijiao Chen"
    },
    {
      "affiliations": [
        "School of Medicine, Chongqing University Cancer Hospital, Chongqing University, Chongqing, People's Republic of China",
        "Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, China"
      ],
      "name": "Xudong Liu"
    },
    {
      "affiliations": [
        "School of Medicine, Chongqing University Cancer Hospital, Chongqing University, Chongqing, People's Republic of China"
      ],
      "name": "Jiongming Chen"
    },
    {
      "affiliations": [
        "School of Medicine, Chongqing University Cancer Hospital, Chongqing University, Chongqing, People's Republic of China"
      ],
      "name": "Liwen Kuang"
    },
    {
      "affiliations": [
        "School of Medicine, Chongqing University Cancer Hospital, Chongqing University, Chongqing, People's Republic of China",
        "Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, China"
      ],
      "name": "Nan Zhang"
    },
    {
      "affiliations": [
        "School of Medicine, Chongqing University Cancer Hospital, Chongqing University, Chongqing, People's Republic of China"
      ],
      "name": "Danyang Li"
    },
    {
      "affiliations": [
        "School of Medicine, Chongqing University Cancer Hospital, Chongqing University, Chongqing, People's Republic of China"
      ],
      "name": "Dan Zhao"
    },
    {
      "affiliations": [
        "School of Medicine, Chongqing University Cancer Hospital, Chongqing University, Chongqing, People's Republic of China"
      ],
      "name": "Dongmei Xue"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, China"
      ],
      "name": "Juan Lei"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, China"
      ],
      "name": "Jiangang Zhang"
    },
    {
      "affiliations": [
        "School of Medicine, Chongqing University Cancer Hospital, Chongqing University, Chongqing, People's Republic of China",
        "Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, China",
        "Chongqing Key Laboratory for the Mechanism and Intervention of Cancer Metastasis, Chongqing, People's Republic of China",
        "Basic Research and Innovation Center for Intelligent Oncology, Ministry of Education, Chongqing, People's Republic of China"
      ],
      "name": "Yongsheng Li"
    },
    {
      "affiliations": [
        "School of Medicine, Chongqing University Cancer Hospital, Chongqing University, Chongqing, People's Republic of China",
        "Department of Medical Oncology, Chongqing University Cancer Hospital, Chongqing, China",
        "Chongqing Key Laboratory for the Mechanism and Intervention of Cancer Metastasis, Chongqing, People's Republic of China",
        "Basic Research and Innovation Center for Intelligent Oncology, Ministry of Education, Chongqing, People's Republic of China"
      ],
      "name": "Lei Wu"
    }
  ],
  "title": "Macrophage CCL7 promotes resistance to immunotherapy for colorectal cancer by regulating the infiltration of macrophages and CD8+ T cells",
  "uid": "8d073028-ae8d-5e0e-8458-9cd22d215bff"
}