{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T14:02:13Z","timestamp":1765375333461,"version":"3.46.0"},"posted":{"date-parts":[[2025,12,8]]},"group-title":"Cancer Biology","reference-count":54,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T00:00:00Z","timestamp":1765152000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"National Cancer Institute (NCI) of the National Institutes of Health","award":["R01 CA262526","P30 CA240139"],"award-info":[{"award-number":["R01 CA262526","P30 CA240139"]}]},{"DOI":"10.13039\/100006827","name":"Florida Department of Health","doi-asserted-by":"crossref","award":["James Esther and King Biomedical Research Program (22K06)","Florida Cancer Innovation Fund (25C22)"],"award-info":[{"award-number":["James Esther and King Biomedical Research Program (22K06)","Florida Cancer Innovation Fund (25C22)"]}],"id":[{"id":"10.13039\/100006827","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,12,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Pancreatic ductal adenocarcinoma (PDAC) remains a challenging disease in need of improved treatments. Cyclic adenosine monophosphate response element binding protein 1 (CREB) is an emerging therapeutic target whose oncogenic effects in PDAC have been largely attributed to a key molecular interplay between oncogenic\n                  <jats:italic>\n                    Kras\n                    <jats:sup>G12D\/+<\/jats:sup>\n                  <\/jats:italic>\n                  (\n                  <jats:italic>Kras*<\/jats:italic>\n                  ) and chronic inflammation driving irreversible acinar to ductal reprogramming. Here, we demonstrate that CREB activation fosters tumor associated macrophage (TAM) mediated immunosuppression and promotes PDAC growth in an aggressive\n                  <jats:italic>\n                    LSL-Kras\n                    <jats:sup>G12D\/+<\/jats:sup>\n                  <\/jats:italic>\n                  ;\n                  <jats:italic>\n                    Trp53\n                    <jats:sup>R172H\/+<\/jats:sup>\n                    ;Pdx1\n                    <jats:sup>Cre\/+<\/jats:sup>\n                  <\/jats:italic>\n                  (\n                  <jats:italic>KPC<\/jats:italic>\n                  ) genetically engineered mouse model. Selective deletion of CREB (\n                  <jats:italic>\n                    Creb\n                    <jats:sup>fl\/fl<\/jats:sup>\n                  <\/jats:italic>\n                  ) in\n                  <jats:italic>KPC<\/jats:italic>\n                  (\n                  <jats:italic>KPCC<\/jats:italic>\n                  <jats:sup>-\/-<\/jats:sup>\n                  ) mice attenuates primary disease burden. Unbiased transcriptomic analysis and validation using diverse molecular, genetic and pharmacological approaches\n                  <jats:italic>in vitro<\/jats:italic>\n                  and\n                  <jats:italic>in vivo<\/jats:italic>\n                  identify CREB-mediated transcriptional regulation of leukemia inhibitory factor (\n                  <jats:italic>Lif<\/jats:italic>\n                  ) as one of the potential mediators of tumor cell-macrophage crosstalk promoting a pro-tumor polarization of TAMs, thereby attenuating the infiltration of effector T cells. Mechanistically, cancer cell derived LIF facilitates an immunosuppressive, pro-tumorigenic state. Importantly, pharmacological targeting of the CREB-LIF signaling axis between cancer cells and macrophages, using a CREB-specific inhibitor (CREBi), significantly suppresses tumor growth and sensitizes PDAC to immunotherapy, highlighting the therapeutic potential of this treatment combination to improve outcomes in this aggressive disease.\n                <\/jats:p>","DOI":"10.64898\/2025.12.04.691935","type":"posted-content","created":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T04:40:18Z","timestamp":1765255218000},"source":"Crossref","is-referenced-by-count":0,"title":["Targeting CREB remodels the immune microenvironment to enhance immunotherapy responses in pancreatic cancer"],"prefix":"10.64898","author":[{"given":"Siddharth","family":"Mehra","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Supriya","family":"Srinivasan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sudhakar","family":"Jinka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Varunkumar","family":"Krishnamoorthy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vineet Kumar","family":"Gupta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vanessa","family":"Garrido","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Bianchi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew M","family":"Adams","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manan","family":"Patel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haleh","family":"Amirian","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luis A","family":"Nivelo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karthik","family":"Rajkumar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rimpi","family":"Khurana","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"suffix":"III","given":"Edmond W","family":"Box","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuguang","family":"Ban","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oliver G","family":"McDonald","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jashodeep","family":"Datta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5749-8394","authenticated-orcid":false,"given":"Kathleen E","family":"DelGiorno","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nipun B","family":"Merchant","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sangeeta","family":"Goswami","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Austin R","family":"Dosch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2373-3293","authenticated-orcid":false,"given":"Nagaraj S","family":"Nagathihalli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025121005350547000_2025.12.04.691935v1.1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21654"},{"key":"2025121005350547000_2025.12.04.691935v1.2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-14-0155"},{"issue":"4","key":"2025121005350547000_2025.12.04.691935v1.3","doi-asserted-by":"crossref","first-page":"e214708-e","DOI":"10.1001\/jamanetworkopen.2021.4708","article-title":"Estimated projection of US cancer incidence and death to 2040","volume":"4","year":"2021","journal-title":"JAMA network open"},{"key":"2025121005350547000_2025.12.04.691935v1.4","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1200694"},{"key":"2025121005350547000_2025.12.04.691935v1.5","doi-asserted-by":"crossref","unstructured":"Kleeff J , Korc M , Apte M , La Vecchia C , Johnson CD , Biankin AV , et al. 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