{
  "abstract": "Background Osteosarcoma is a highly aggressive cancer, and the efficacy of existing therapies has plateaued. Multiomics integration analysis can identify novel therapeutic targets for various cancers and therefore shows potential toward osteosarcoma treatment. This study aimed to leverage multiomics integration to develop a new risk model, characterizing the immune features of osteosarcoma to uncover novel therapeutic targets.Methods Metabolomics profiling was conducted to identify key metabolites in osteosarcoma. Transcriptomic sequencing datasets were analyzed to identify prognostic genes related to key metabolic pathways and develop a prognostic risk model. Patients were then divided into high-risk and low-risk groups with distinct clinical outcomes based on the risk model. The single-sample gene set enrichment analysis, Estimation of Stromal and Immune cells in Malignant Tumor tissues using Expression data (ESTIMATE) algorithm, and xCell algorithms were used to evaluate the immune cell infiltration and activity. Single-cell RNA sequencing was used to explore cell-to-cell interactions within the tumor microenvironment. In vitro coculture functional assays were performed to validate the role of macrophage migration inhibitory factor (MIF) in macrophage polarization and chemotaxis. In vivo studies were used to evaluate the effectiveness of MIF inhibition in combination with immune checkpoint blockade in murine models.Results Elevated lactate levels in osteosarcoma patients correlated with poorer overall survival. We identified SLC7A7 and CYP27A1 as prognostic lactate metabolism genes and developed a risk model to stratify patients into high-risk and low-risk groups with distinct outcomes. Bioinformatics analyses highlighted the differences in immune infiltration patterns and activity between the groups. Notably, the infiltration and phenotype of macrophages varied significantly between the groups, and MIF was identified as a critical mediator in this process. In osteosarcoma cells, lactate regulated MIF expression through histone H3K9 lactylation. Combining the MIF inhibitor 4-IPP with a programmed cell death 1 (PD-1) monoclonal antibody treatment demonstrated a significant antitumor effect.Conclusion MIF acts as a novel therapeutic target by regulating macrophage polarization and chemotaxis. Lactate regulated MIF expression through histone lactylation. Targeting MIF holds promise for enhancing the efficacy of anti-PD-1 treatment.",
  "authors": [
    {
      "affiliations": [
        "Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China",
        "Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Guangzhou, China"
      ],
      "name": "Weidong Chen"
    },
    {
      "affiliations": [
        "Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China",
        "Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Guangzhou, China"
      ],
      "name": "Yan Liao"
    },
    {
      "affiliations": [
        "Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China",
        "Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Guangzhou, China"
      ],
      "name": "Hao Yao"
    },
    {
      "affiliations": [
        "Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China",
        "Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Guangzhou, China"
      ],
      "name": "Yutong Zou"
    },
    {
      "affiliations": [
        "Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China",
        "Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Guangzhou, China"
      ],
      "name": "Ji Fang"
    },
    {
      "affiliations": [
        "Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China",
        "Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Guangzhou, China"
      ],
      "name": "Jiongfeng Zhang"
    },
    {
      "affiliations": [
        "Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China",
        "Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Guangzhou, China"
      ],
      "name": "Zehao Guo"
    },
    {
      "affiliations": [
        "Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China",
        "Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Guangzhou, China"
      ],
      "name": "Jian Tu"
    },
    {
      "affiliations": [
        "Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China",
        "Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Guangzhou, China"
      ],
      "name": "Junkai Chen"
    },
    {
      "affiliations": [
        "Department of Endocrinology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China"
      ],
      "name": "Zijun Huo"
    },
    {
      "affiliations": [
        "Department of Anesthesiology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China"
      ],
      "name": "Lili Wen"
    },
    {
      "affiliations": [
        "Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China",
        "Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Guangzhou, China"
      ],
      "name": "Xianbiao Xie"
    }
  ],
  "title": "Multiomics integration analysis identifies tumor cell-derived MIF as a therapeutic target and potentiates anti-PD-1 therapy in osteosarcoma",
  "uid": "f41d5ca2-10ba-5c72-a6d4-69c21cedac2e"
}