{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T02:49:04Z","timestamp":1793155744702,"version":"4.5.0"},"reference-count":56,"publisher":"BMJ","issue":"8","license":[{"start":{"date-parts":[[2023,8,28]],"date-time":"2023-08-28T00:00:00Z","timestamp":1693180800000},"content-version":"unspecified","delay-in-days":27,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2023,7,21]]},"published-print":{"date-parts":[[2023,8]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Localized radiotherapy (RT) can cause a T cell-mediated abscopal effect on non-irradiated tumor lesions, especially in combination with immune checkpoint blockade. However, this effect is still clinically rare and improvements are highly desirable. We investigated whether triple combination with a low dose of clinically approved liposomal doxorubicin (Doxil) could augment abscopal responses compared with RT\/\u03b1PD-1 and Doxil\/\u03b1PD-1. We also investigated whether the enhanced abscopal responses depended on the mitochondrial DNA (mtDNA)\/cyclic GMP-AMP synthase (cGAS)\/stimulator of interferon genes (STING)\/IFN-I pathway.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials\/methods<\/jats:title>\n                    <jats:p>We used Doxil in combination with RT and \u03b1PD-1 in two tumor models (B16-CD133 melanoma and MC38 colon carcinoma) with mice bearing two tumors, only one of which was irradiated. Mechanistic studies on the role of the mtDNA\/cGAS\/STING\/IFN-I axis were performed using inhibitors and knockout cells in vitro as well as in mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Addition of a single low dose of Doxil to RT and \u03b1PD-1 strongly enhanced the RT\/\u03b1PD-1-induced abscopal effect in both models. Complete cures of non-irradiated tumors were mainly observed in triple-treated mice. Triple therapy induced more cross-presenting dendritic cells (DCs) and more tumor-specific CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells than RT\/\u03b1PD-1 and Doxil\/\u03b1PD-1, particularly in non-irradiated tumors. Coincubation of Doxil-treated and\/or RT-treated tumor cells with DCs enhanced DC antigen cross-presentation which is crucial for inducing CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells. CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell depletion or implantation of cGAS-deficient or STING-deficient tumor cells abolished the abscopal effect. Doxorubicin-induced\/Doxil-induced IFN\u03b21 markedly depended on the cGAS\/STING pathway. Doxorubicin-treated\/Doxil-treated tumor cells depleted of mtDNA secreted less IFN\u03b21, of the related T cell-recruiting chemokine CXCL10, and ATP; coincubation with mtDNA-depleted tumor cells strongly reduced IFN\u03b21 secretion by DCs. Implantation of mtDNA-depleted tumor cells, particularly at the non-irradiated\/abscopal site, substantially diminished the Doxil-enhanced abscopal effect and tumor infiltration by tumor-specific CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      These data show that single low-dose Doxil can substantially enhance the RT\/\u03b1PD-1-induced abscopal effect, with a strong increase in cross-presenting DCs and CD8\n                      <jats:sup>+<\/jats:sup>\n                      tumor-specific T cells particularly in abscopal tumors compared with RT\/\u03b1PD-1 and Doxil\/\u03b1PD-1. Moreover, they indicate that the mtDNA\/cGAS\/STING\/IFN-I axis is important for the immunogenic\/immunomodulatory doxorubicin effects. Our \ufb01ndings may be helpful for the planning of clinical radiochemoimmunotherapy trials in (oligo)metastatic patients.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2022-006235","type":"journal-article","created":{"date-parts":[[2023,8,28]],"date-time":"2023-08-28T12:45:12Z","timestamp":1693226712000},"page":"e006235","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":43,"title":["Adding liposomal doxorubicin enhances the abscopal effect induced by radiation\/\u03b1PD1 therapy depending on tumor cell mitochondrial DNA and cGAS\/STING"],"prefix":"10.1136","volume":"11","clinical-trial-number":[{"clinical-trial-number":"nct03164993","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct03598270","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Liqun","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Radiation Oncology, University of 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