{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:18:41Z","timestamp":1792790321028,"version":"4.5.0"},"posted":{"date-parts":[[2026,9,30]]},"group-title":"Immunology","reference-count":40,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"National Cancer Institute","award":["P30CA034196"],"award-info":[{"award-number":["P30CA034196"]}]},{"name":"National Heart Lung and Blood Institute","award":["R01HL148153"],"award-info":[{"award-number":["R01HL148153"]}],"id":[{"id":"https:\/\/ror.org\/012pb6c26","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Cancer Prevention and Research Institute of Texas","award":["RP170734"],"award-info":[{"award-number":["RP170734"]}],"id":[{"id":"https:\/\/ror.org\/0003xa228","id-type":"ROR","asserted-by":"crossref"}]},{"name":"American Cancer Society","award":["PF-26-1594975-01"],"award-info":[{"award-number":["PF-26-1594975-01"]}],"id":[{"id":"https:\/\/ror.org\/02e463172","id-type":"ROR","asserted-by":"crossref"}]},{"name":"American Cancer Society","award":["PF-25-1420432-01"],"award-info":[{"award-number":["PF-25-1420432-01"]}],"id":[{"id":"https:\/\/ror.org\/02e463172","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,30]]},"abstract":"<jats:title>\n                  <jats:bold>Abstract<\/jats:bold>\n                <\/jats:title>\n                <jats:p>\n                  Mitochondrial DNA (mtDNA) instability is an emerging feature of cancer, yet its biological effects on the tumor microenvironment (TME) and tumor progression remain incompletely defined. Using melanocyte-specific conditional silencing of mitochondrial transcription factor A (TFAM) in an autochthonous\n                  <jats:italic>\n                    Braf\n                    <jats:sup>V600E<\/jats:sup>\n                  <\/jats:italic>\n                  \/\n                  <jats:italic>\n                    Pten\n                    <jats:sup>-\/-<\/jats:sup>\n                  <\/jats:italic>\n                  melanoma model, we demonstrate that tumor cell-intrinsic mtDNA instability accelerates melanoma growth and metastatic dissemination in a cGAS-dependent manner. Transcriptomic profiling of early and late tumor stages revealed that mtDNA instability drives temporal remodeling of the tumor microenvironment (TME), characterized by an early type I interferon (IFN)-rich inflammatory state that licenses immunoregulatory programs as tumors progress. Tumor-associated macrophages emerged as the principal immune cell type reshaped by tumor cell-intrinsic mtDNA stress signaling, with early enrichment of inflammatory states and a shift toward efferocytosis-associated, tissue-adaptive states. The early mtDNA instability-associated macrophage signatures mapped to human melanoma states associated with favorable survival and therapy response, whereas the late signatures mapped to states associated with poor prognosis and therapy resistance across independent cohorts. Anti-PD-1 treatment delayed progression of mtDNA-instable tumors, consistent with a therapeutic sensitivity window associated with the early IFN-rich immune state. These findings establish tumor cell-intrinsic mtDNA instability as a driver of temporal immune-stromal remodeling that promotes melanoma progression and shapes therapeutic response.\n                <\/jats:p>","DOI":"10.64898\/2026.09.28.755003","type":"posted-content","created":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T05:28:40Z","timestamp":1791091720000},"source":"Crossref","is-referenced-by-count":0,"title":["Tumor cell-intrinsic mtDNA instability drives cGAS-dependent temporal remodeling of the melanoma immune microenvironment"],"prefix":"10.64898","author":[{"given":"Abate Assefa","family":"Bashaw","sequence":"first","affiliation":[{"name":"The Jackson Laboratory, Bar Harbor, ME 04609, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley D.","family":"Winters","sequence":"additional","affiliation":[{"name":"Texas A&M University College of Medicine, Bryan, TX, 77807, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanjiu","family":"Lei","sequence":"additional","affiliation":[{"name":"Texas A&M University College of Medicine, Bryan, TX, 77807, USA"},{"name":"Yale School of Medicine, New Haven, CT, 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luiza Ferreira","family":"Araujo","sequence":"additional","affiliation":[{"name":"Texas A&M University College of Medicine, Bryan, TX, 77807, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Do Gia","family":"Tam Vo","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory, Bar Harbor, ME 04609, USA"},{"name":"Genetics, Molecular and Cellular Biology Graduate Program, Graduate School of Biomedical Sciences, Tufts University, Boston, MA 02111, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arunachalam","family":"Sekar","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory, Bar Harbor, ME 04609, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John F.","family":"Bachman","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory, Bar Harbor, ME 04609, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paige S.","family":"Graves","sequence":"additional","affiliation":[{"name":"Texas A&M University College of Medicine, Bryan, TX, 77807, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa","family":"Pineda","sequence":"additional","affiliation":[{"name":"Texas A&M University College of Medicine, Bryan, TX, 77807, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jill C.","family":"Rubinstein","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory, Bar Harbor, ME 04609, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerald S.","family":"Shadel","sequence":"additional","affiliation":[{"name":"Salk Institute for Biological Studies, La Jolla, CA, 92037, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus","family":"Bosenberg","sequence":"additional","affiliation":[{"name":"Yale School of Medicine, New Haven, CT, 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura Ciaccia","family":"West","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory, Bar Harbor, ME 04609, USA"},{"name":"Texas A&M University College of Medicine, Bryan, TX, 77807, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2884-6895","authenticated-orcid":false,"given":"A. 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