{
  "abstract": "Background Patients with colon cancer liver metastases (CCLM) frequently exhibit poor responses to immunotherapy, a phenomenon attributed in part to an immune desert tumor microenvironment. This study aimed to comprehensively characterize the immune landscape in primary colon cancers and their matched liver metastases via single-cell transcriptome analysis, with the goal of identifying potential immunotherapeutic targets.Methods Tumor specimens from patients with CCLM were subjected to single-cell RNA sequencing. Immune subpopulations were profiled with emphasis on exhausted T cells (Tex)—including both CD8 + and CD4+ ANK3+ subsets—as well as on a distinct stress response T-cell subset (TSTR) defined by high HSPA1A/HSPA1B expression. In parallel, we performed assessments of the phenotype and prognostic impact of SPP1high myeloid cells, along with in vitro assays to examine their role in modulating T-cell number and function.Results Liver metastatic lesions exhibited a significantly elevated infiltration of Tex compared with primary tumors. Notably, Tex cells exhibited upregulated expression of exhaustion-related marker genes such as ANK3, ZBTB20, ETV6, and CAMK4, which were markedly downregulated in TSTR cells. TSTR was identified as an intermediate developmental state between effector and exhausted T cells in patients with CCLM, suggesting that TSTR cells represent a distinct state from exhausted T cells. Furthermore, myeloid cells expressing high levels of secreted phosphoprotein 1 (SPP1), along with apolipoprotein C-I and apolipoprotein E, were associated with poor prognosis in patients with CCLM. In vitro studies revealed that Macro_SPP1high cells diminished T-cell populations and triggered a stress response state in both CD4+ and CD8+ T cells via the SPP1/CD44/PI3K/AKT signaling pathway in a CD44-dependent manner. Importantly, combination treatment with anti-SPP1 and anti-programmed cell death protein-1 antibodies significantly inhibited liver metastasis growth, enhanced dendritic cell maturation, decreased M2-polarized macrophages, and restored T-cell infiltration and function.Conclusions These findings reveal a previously unrecognized relationship between Macro_SPP1 high cells and HSPA1Ahigh/HSPA1Bhigh T cells in driving CCLM progression, suggesting a potential synergistic therapeutic approach that could boost immune checkpoint treatment efficacy in patients with CCLM.",
  "authors": [
    {
      "affiliations": [
        "Department of Gastrointestinal Surgery, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China"
      ],
      "name": "Dongbing Ding"
    },
    {
      "affiliations": [
        "Department of Gastrointestinal Surgery, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China"
      ],
      "name": "Weibo Li"
    },
    {
      "affiliations": [
        "Department of Gastrointestinal Surgery, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China"
      ],
      "name": "Jiannan Ren"
    },
    {
      "affiliations": [
        "Department of Gastrointestinal Surgery, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China"
      ],
      "name": "Yiquan Li"
    },
    {
      "affiliations": [
        "Department of Gastrointestinal Surgery, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China"
      ],
      "name": "Guangchun Jiang"
    },
    {
      "affiliations": [
        "Department of Gastrointestinal Surgery, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China"
      ],
      "name": "Rongpu Liang"
    },
    {
      "affiliations": [
        "Department of Gastrointestinal Surgery, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China"
      ],
      "name": "He Huang"
    },
    {
      "affiliations": [
        "Department of Gastrointestinal Surgery, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China"
      ],
      "name": "Jiarong You"
    },
    {
      "affiliations": [
        "Department of Gastrointestinal Surgery, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China"
      ],
      "name": "Yuan Wang"
    },
    {
      "affiliations": [
        "Department of Gastrointestinal Surgery, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China"
      ],
      "name": "Bo Wei"
    }
  ],
  "title": "SPP1high macrophage-induced T-cell stress promotes colon cancer liver metastasis through SPP1/CD44/PI3K/AKT signaling",
  "uid": "5e6e7322-adcd-56fc-a3b4-7cbda9befe20"
}