{
  "abstract": "Background Despite comparable survival benefit has been obtained, the drug resistance remarkably reduced lenvatinib clinical efficacy. Here, we aimed to identify the potential mechanism by which cysteine and glycine-rich protein 2 (CSRP2) regulates the development of hepatocellular carcinoma (HCC) and participates in the resistance to lenvatinib.Methods We harnessed RNA sequencing, multiplex immunofluorescence staining, and hydrodynamic tail vein (HTV) injection HCC model to systematically explore the function of CSRP2 in HCC progression. To precisely delineate how immunosuppressive macrophages, influenced by CSRP2-regulated C-C motif chemokine ligand 28 (CCL28) signaling, respond to lenvatinib-induced cytotoxicity, we established an in vitro co-culture system and conducted functional cytotoxicity assays.Results Using RNA sequencing, multiplex immunofluorescence staining and HTV injection HCC mouse model, we identified CSRP2 as one of the most significantly upregulated genes in HCC tissues. CSRP2 overexpression drives anti-lenvatinib resistance by inducing high levels of tumor-associated macrophages (TAMs) infiltration and reshaping an immunosuppressive microenvironment. Then flow cytometry, mass spectrometry and chromatin immunoprecipitation were conducted to clarify the underlying mechanism of CSRP2. We showed CSRP2 promotes phosphorylation of activating transcription factor 2 (ATF2) at Thr69/71, leading to the transcriptional activation of CCL28 expression. HCC-derived CCL28 recruits TAMs to drive immunosuppression and anti-lenvatinib tolerance. BI6901, a potent and selective CCR10 antagonist, blocked TAMs recruitment and enhanced T-cell activation. Combining CCR10 inhibition improved the therapeutic benefit of anti-lenvatinib in HCC.Conclusions These results illustrate that CSRP2 regulates the tumor microenvironment to promote HCC growth and drive lenvatinib tolerance via the CSRP2/ATF2/CCL28 axis. Targeting this pathway could synergize with lenvatinib to treat HCC more effectively.",
  "authors": [
    {
      "affiliations": [
        "Department of Hepatobiliary Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, Shanghai, China",
        "Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Zhongshan Hospital, Fudan University, Shanghai, Shanghai, China"
      ],
      "name": "Changzhou Chen"
    },
    {
      "affiliations": [
        "Department of Hepatobiliary Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, Shanghai, China",
        "Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Zhongshan Hospital, Fudan University, Shanghai, Shanghai, China"
      ],
      "name": "Sheng Su"
    },
    {
      "affiliations": [
        "Department of Gynecologic Oncology, Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China"
      ],
      "name": "Pengcheng Wang"
    },
    {
      "affiliations": [
        "Department of Hepatobiliary Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, Shanghai, China",
        "Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Zhongshan Hospital, Fudan University, Shanghai, Shanghai, China"
      ],
      "name": "Xinming Ye"
    },
    {
      "affiliations": [
        "Department of Colorectal Surgery, Zhejiang University School of Medicine, Hangzhou, China"
      ],
      "name": "Songyang Yu"
    },
    {
      "affiliations": [
        "Department of Hepatobiliary Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, Shanghai, China",
        "Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Zhongshan Hospital, Fudan University, Shanghai, Shanghai, China"
      ],
      "name": "Yu Gong"
    },
    {
      "affiliations": [
        "Department of Hepatobiliary Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, Shanghai, China",
        "Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Zhongshan Hospital, Fudan University, Shanghai, Shanghai, China"
      ],
      "name": "Zehuan Li"
    },
    {
      "affiliations": [
        "Department of Thoracic Surgery, Shanghai Jiao Tong University School of Medicine, Shanghai, China"
      ],
      "name": "Jia Li"
    },
    {
      "affiliations": [
        "Department of Hepatobiliary Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, Shanghai, China",
        "Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Zhongshan Hospital, Fudan University, Shanghai, Shanghai, China"
      ],
      "name": "Zhiqiang Hu"
    },
    {
      "affiliations": [
        "Department of Hepatobiliary Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, Shanghai, China",
        "Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Zhongshan Hospital, Fudan University, Shanghai, Shanghai, China",
        "Clinical Center for Biotherapy, Zhongshan Hospital, Fudan University, Shanghai, Shanghai, China"
      ],
      "name": "Xiaowu Huang"
    }
  ],
  "title": "Targeting immunosuppressive macrophages by CSRP2-regulated CCL28 signaling sensitizes hepatocellular carcinoma to lenvatinib",
  "uid": "3ba6b1a5-d421-5113-ba79-6d7b7bf2e1e7"
}