{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T14:00:52Z","timestamp":1782741652486,"version":"3.54.5"},"reference-count":27,"publisher":"BMJ","issue":"6","license":[{"start":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T00:00:00Z","timestamp":1782691200000},"content-version":"unspecified","delay-in-days":28,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004917","name":"Cancer Prevention and Research Institute of Texas","doi-asserted-by":"publisher","award":["RP180684"],"award-info":[{"award-number":["RP180684"]}],"id":[{"id":"10.13039\/100004917","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","award":["R01CA247862"],"award-info":[{"award-number":["R01CA247862"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Lantern Pharma Inc.","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"name":"National Institutes of Health\/National Cancer Institute","award":["P30CA016672"],"award-info":[{"award-number":["P30CA016672"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2026,6,8]]},"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Transcriptomic signatures of\n                      <jats:italic>TREX1<\/jats:italic>\n                      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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      An in vivo TREX1-deficiency transcriptional signature, reflecting ssDNA-driven immune programs rather than\n                      <jats:italic>TREX1<\/jats:italic>\n                      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\n                      <jats:sup>+<\/jats:sup>\n                      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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2025-014722","type":"journal-article","created":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T13:30:21Z","timestamp":1782739821000},"page":"e014722","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Chemotherapeutic induction of cytosolic single-stranded DNA accumulation sensitizes triple-negative breast cancer to immunotherapy"],"prefix":"10.1136","volume":"14","author":[{"given":"Yong","family":"Du","sequence":"first","affiliation":[{"name":"Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Baylor College of Medicine, 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