{
  "abstract": "Background Despite the widespread adoption of chemoimmunotherapy in triple-negative breast cancer (TNBC), the mechanisms by which cytotoxic chemotherapy engages antitumor immunity remain poorly defined. Identifying tumor-intrinsic immunogenic programs that predict and enhance responsiveness to immune checkpoint blockade (ICB) is therefore of critical clinical importance.Methods Transcriptomic signatures of TREX1 deficiency were generated from CRISPR-engineered TNBC models and applied to multiple independent TNBC cohorts treated with chemoimmunotherapy. Cytosolic single-stranded DNA (ssDNA) accumulation was quantified using a flow cytometry-based assay to functionally screen chemotherapeutic agents. Immune activation and therapeutic efficacy were evaluated using in vitro assays, syngeneic mouse tumor models, flow cytometry, and single-cell RNA sequencing. Statistical analyses included two-sided t tests or Wilcoxon tests, analysis of variance where appropriate, and receiver operating characteristic analyses.Results An in vivo TREX1-deficiency transcriptional signature, reflecting ssDNA-driven immune programs rather than TREX1 expression alone, robustly predicted clinical response to chemoimmunotherapy across independent TNBC cohorts. Functional screening identified LP-184, an acylfulvene-derived alkylating agent in clinical development, as a potent inducer of cytosolic ssDNA and type I interferon signaling. LP-184 enhanced antigen presentation, reduced immunosuppressive M2-like macrophages, promoted CD8+ T-cell priming, and synergized with anti-programmed cell death protein 1 therapy in vivo. Exogenous ssDNA recapitulated key immunostimulatory effects of LP-184, supporting ssDNA accumulation as a central mechanistic mediator.Conclusions These findings establish cytosolic ssDNA-driven immune programs as a mechanistic link between DNA damage and antitumor immunity, providing both a predictive biomarker and a therapeutic axis for chemoimmunotherapy. Pharmacologic induction of ssDNA represents a rational strategy to enhance ICB efficacy and expand immunotherapy responsiveness in TNBC.",
  "authors": [
    {
      "affiliations": [
        "Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Yong Du"
    },
    {
      "affiliations": [
        "Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA"
      ],
      "name": "Li Yang"
    },
    {
      "affiliations": [
        "Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Hui Dai"
    },
    {
      "affiliations": [
        "Lantern Pharma Inc, Dallas, Texas, USA"
      ],
      "name": "Jianli Zhou"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Zhicheng Zhou"
    },
    {
      "affiliations": [
        "Hospital for Special Surgery, New York, New York, USA"
      ],
      "name": "Ruoxi Yuan"
    },
    {
      "affiliations": [
        "Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Rui Ye"
    },
    {
      "affiliations": [
        "Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Anh Thai Quynh Nguyen"
    },
    {
      "affiliations": [
        "Lantern Pharma Inc, Dallas, Texas, USA"
      ],
      "name": "Kishor Bhatia"
    },
    {
      "affiliations": [
        "Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Shiaw-Yih Lin"
    }
  ],
  "title": "Chemotherapeutic induction of cytosolic single-stranded DNA accumulation sensitizes triple-negative breast cancer to immunotherapy",
  "uid": "9f9040ca-fba0-5f2c-86f9-1c1f73e8246d"
}