Language
English
Publication Date
6-29-2026
Journal
The Journal for ImmunoTherapy of Cancer
DOI
10.1136/jitc-2025-014722
PMID
42373131
PMCID
PMC13331146
PubMedCentral® Posted Date
6-29-2026
PubMedCentral® Full Text Version
Post-print
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.
Keywords
Triple Negative Breast Neoplasms, Animals, Humans, Female, Immunotherapy, Mice, DNA, Single-Stranded, Cytosol, Cell Line, Tumor, Chemotherapy, Immunotherapy, Breast Cancer, Biomarker
Published Open-Access
yes
Recommended Citation
Du, Yong; Yang, Li; Dai, Hui; et al., "Chemotherapeutic Induction of Cytosolic Single-Stranded DNA Accumulation Sensitizes Triple-Negative Breast Cancer to Immunotherapy" (2026). Faculty, Staff and Students Publications. 7744.
https://digitalcommons.library.tmc.edu/baylor_docs/7744