{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,6]],"date-time":"2026-06-06T13:01:10Z","timestamp":1780750870033,"version":"3.54.1"},"posted":{"date-parts":[[2026,6,3]]},"group-title":"Cancer Biology","reference-count":47,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T00:00:00Z","timestamp":1780444800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"National Cancer Institute","award":["R01 CA288849"],"award-info":[{"award-number":["R01 CA288849"]}]},{"name":"National Cancer Institute","award":["R01 CA288849"],"award-info":[{"award-number":["R01 CA288849"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,3]]},"abstract":"<jats:title>SUMMARY<\/jats:title>\n                <jats:p>Mono-ADP-ribosylation (MARylation) is emerging as an important regulator of anti-cancer immunity and immunosuppressive tumor microenvironment (TME). Our previous studies showed that PARP11, one of several enzymes that facilitate MARylation, regulates the activities of intratumoral cytotoxic T lymphocytes (CTLs) and regulatory T cells (Tregs). Here, we demonstrate that stimuli such as adenosine, epinephrine, or glucagon-like peptide-1 (GLP1) induced PARP11 in cancer cells. Upregulation of PARP11 in cancer cells led to PARP11-mediated MARylation, ubiquitination, and accelerated degradation of MHC-I through the autophagy-lysosomal pathway. Induction of PARP11 protected cancer cells from killing by specific CTLs and stimulated tumor growth and progression. Genetic ablation of PARP11 attenuated MHC-I MARylation, ubiquitination, and interaction with autophagy receptors. Pharmacologic inhibition of PARP11 in pancreatic ductal adenocarcinoma (PDAC) cells restored their MHC-I levels, sensitized them to killing by CTLs, inhibited tumor growth, and impeded their initial resistance to chemotherapy and their acquired resistance to targeted therapy with RAS inhibitors. Moreover, inhibition of PARP11 prevented hyperprogressive disease in a mouse melanoma model treated with immune checkpoint inhibitors (ICBs), suggesting that PARP11 is a major therapeutically actionable driver of immunosuppression in tumors.<\/jats:p>\n                <jats:sec>\n                  <jats:title>SYNOPSIS<\/jats:title>\n                  <jats:p>Induction of PARP11 in the tumor microenvironment mediates immunosuppression. This study reports that PARP11-driven MARylation and ubiquitination of MHC-I in cancer cells drives immune evasion, tumor growth and resistance to therapies.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.06.01.729331","type":"posted-content","created":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T13:25:14Z","timestamp":1780493114000},"source":"Crossref","is-referenced-by-count":0,"title":["Mono-ADP-ribosylation-driven immunosuppression and cross-resistance to therapy through cancer cell intrinsic and extrinsic mechanisms"],"prefix":"10.64898","author":[{"given":"Yuchen","family":"Sun","sequence":"first","affiliation":[{"name":"Dept. of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingying","family":"Tang","sequence":"additional","affiliation":[{"name":"Dept. of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivek T.","family":"Singh","sequence":"additional","affiliation":[{"name":"Dept. of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c1gnes","family":"Holczbauer","sequence":"additional","affiliation":[{"name":"Dept. of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raghavendra","family":"Basavaraja","sequence":"additional","affiliation":[{"name":"Dept. of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quoc Thang","family":"Bui","sequence":"additional","affiliation":[{"name":"Dept. of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeong-Hwa","family":"Lee","sequence":"additional","affiliation":[{"name":"Dept. of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"name":"Laboratory of Veterinary Nutrition, College of Veterinary Medicine, Seoul National University, Seoul 08826, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Runnan","family":"Gao","sequence":"additional","affiliation":[{"name":"Dept. of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. 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Alan","family":"Diehl","sequence":"additional","affiliation":[{"name":"Dept. of Biochemistry, Case Western Reserve University, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Fan","sequence":"additional","affiliation":[{"name":"Dept of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Constantinos","family":"Koumenis","sequence":"additional","affiliation":[{"name":"Dept of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timour","family":"Baslan","sequence":"additional","affiliation":[{"name":"Dept. of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0410-4037","authenticated-orcid":false,"given":"Ben Z.","family":"Stanger","sequence":"additional","affiliation":[{"name":"Dept. of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael S.","family":"Cohen","sequence":"additional","affiliation":[{"name":"Dept. of Chemical Physiology and Biochemistry, Oregon Health & Science University Portland, OR 97239, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladimir S.","family":"Spiegelman","sequence":"additional","affiliation":[{"name":"Division of Pediatric Hematology and Oncology, Dept. of Pediatrics, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0136-5103","authenticated-orcid":false,"given":"Serge Y.","family":"Fuchs","sequence":"additional","affiliation":[{"name":"Dept. of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026060605350809000_2026.06.01.729331v1.1","doi-asserted-by":"crossref","unstructured":"Jhunjhunwala S , Hammer C , Delamarre L . 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