Phosphines-Nitrogen-Phosphines chelated CoCl2 is a novel therapeutic agent for pancreatic cancer

Phosphines-Nitrogen-Phosphines chelated CoCl2 is a novel therapeutic agent for pancreatic cancer | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Phosphines-Nitrogen-Phosphines chelated CoCl 2 is a novel therapeutic agent for pancreatic cancer Xuefei Guo, Yang Zhao, Xianle Rong, Xingyu Chen, Xiao Wang, Tianyi Liu, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6476256/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Pancreatic cancer is projected to become the second leading cause of cancer-related deaths globally by 2030, yet effective therapeutic options remain limited. Within the pancreatic cancer tumor microenvironment (TME), tumor-associated macrophages (TAMs) secrete interleukin-1 beta (IL-1β), promoting cancer progression while suppressing type I interferons (IFN-I), which is critical for tumor killing. Utilizing the convolutional neural network (CNN)-based DLINP model developed in our laboratory, we identified Co68—an effective metal catalyst featuring a Phosphines-Nitrogen-Phosphines (PNP)-chelated CoCl₂ complex—as a promising candidate to modulate innate immune responses. In animal models of pancreatic cancer, Co68 demonstrated superior antitumor efficacy compared to the STING agonist DMXAA and showed enhanced therapeutic effects when combined with PD-1 blockade. Single-cell RNA sequencing (scRNA-seq) revealed that Co68 reprogramed TAMs to express interferon-stimulated genes (ISGs), attenuated pro-inflammatory cytokine secretion, and disrupted the IL-1β-PGE2 feedback loop, thereby facilitating the recruitment of NK and cytotoxic CD8+ T cells into the TME. Mechanistically, Co68 activated the IFN-I signaling pathway through the TLR4-TRIF-IFN-I axis and inhibited inflammation via the TLR4-SYK-STAT1 pathway. Collectively, these findings highlight the therapeutic potential of Co68, derived from PNP-pincer chemistry, to reshape immune dynamics within the pancreatic cancer TME, positioning it as a promising candidate for innovative immunotherapy strategies. Biological sciences/Immunology/Innate immunity/Pattern recognition receptors/Toll-like receptors Biological sciences/Drug discovery/Drug screening/High-throughput screening Biological sciences/Immunology/Immune evasion Biological sciences/Cancer/Cancer microenvironment Biological sciences/Cancer/Cancer therapy/Cancer immunotherapy Pancreatic ductal adenocarcinoma (PDAC) Inflammatory response Innate immunity response Convolutional neural network Phosphines-Nitrogen-Phosphines (PNP)-pincer ligands TLR4 STAT1 NF-κB Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementaryMaterials.zip Supplementary Materials Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6476256","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":444951480,"identity":"f7b76201-1ec3-4a18-86c0-59f336ab9224","order_by":0,"name":"Xuefei Guo","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0UlEQVRIiWNgGAWjYLCCigoJOfv2xsaHH4jWcuaMjbEBz+FmYwmitZxtS0vcIJHeJsBDjGr5iORjEgfYDjNul3zYxiDBYCen20BAi+GNtGSDAzyHmS1nJ7Y9KGBINjY7QEjLjBzDxx8kDrMx3E5sN5BgOJC4jQgtBgcOGBzmYbh5sE2Chxgt8hI5hg8OJKRJGNxgJFKLAc8zoF8O2BhI9iQCA9mACL/ItwND7OA/ifp+9uMPH36osJMjqMUAVYEBAeVgWxqIUDQKRsEoGAUjHAAAZ3lHYXMurKUAAAAASUVORK5CYII=","orcid":"","institution":"Peking University Health Science Center","correspondingAuthor":true,"prefix":"","firstName":"Xuefei","middleName":"","lastName":"Guo","suffix":""},{"id":444951481,"identity":"f5220040-c60e-4de2-8a0e-c8b4c7936c15","order_by":1,"name":"Yang Zhao","email":"","orcid":"","institution":"Department of Microbiology \u0026 Infectious Disease Center, NHC Key Laboratory of Medical Immunology, Peking University Health Science Center, Peking University","correspondingAuthor":false,"prefix":"","firstName":"Yang","middleName":"","lastName":"Zhao","suffix":""},{"id":444951482,"identity":"da11b930-0f88-4257-a220-20191f1c8e19","order_by":2,"name":"Xianle Rong","email":"","orcid":"","institution":"Tsinghua University","correspondingAuthor":false,"prefix":"","firstName":"Xianle","middleName":"","lastName":"Rong","suffix":""},{"id":444951483,"identity":"f9878ea2-85d0-4f68-897d-9583157b43a1","order_by":3,"name":"Xingyu Chen","email":"","orcid":"","institution":"Department of Microbiology \u0026 Infectious Disease Center, NHC Key Laboratory of Medical Immunology, Peking University Health Science Center, Peking University","correspondingAuthor":false,"prefix":"","firstName":"Xingyu","middleName":"","lastName":"Chen","suffix":""},{"id":444951484,"identity":"f46883d7-8b44-4352-836c-3c147a74c161","order_by":4,"name":"Xiao Wang","email":"","orcid":"","institution":"Peking University","correspondingAuthor":false,"prefix":"","firstName":"Xiao","middleName":"","lastName":"Wang","suffix":""},{"id":444951485,"identity":"74fead10-f6bb-4b46-ae26-97dd95f69733","order_by":5,"name":"Tianyi Liu","email":"","orcid":"","institution":"Peking University","correspondingAuthor":false,"prefix":"","firstName":"Tianyi","middleName":"","lastName":"Liu","suffix":""},{"id":444951486,"identity":"d93f43cc-b533-4fff-87cc-814819844606","order_by":6,"name":"Yunfei Xiao","email":"","orcid":"","institution":"Peking University","correspondingAuthor":false,"prefix":"","firstName":"Yunfei","middleName":"","lastName":"Xiao","suffix":""},{"id":444951487,"identity":"04877f37-132c-4564-b2c0-b05fd8ca4e53","order_by":7,"name":"Yushu Zou","email":"","orcid":"","institution":"Peking University","correspondingAuthor":false,"prefix":"","firstName":"Yushu","middleName":"","lastName":"Zou","suffix":""},{"id":444951488,"identity":"7bba5bf7-05f0-471d-a45a-028e44006ed0","order_by":8,"name":"Tianming Chu","email":"","orcid":"","institution":"Chinese Academy of Sciences","correspondingAuthor":false,"prefix":"","firstName":"Tianming","middleName":"","lastName":"Chu","suffix":""},{"id":444951489,"identity":"2fd91c6a-147d-407f-9054-2e6001d5bef1","order_by":9,"name":"Xiangxi Wang","email":"","orcid":"","institution":"Chinese Academy of Sciences","correspondingAuthor":false,"prefix":"","firstName":"Xiangxi","middleName":"","lastName":"Wang","suffix":""},{"id":444951490,"identity":"d5b7cef8-e200-45ec-a6fc-5f38971ac39e","order_by":10,"name":"Qiang Liu","email":"","orcid":"","institution":"Tsinghua University","correspondingAuthor":false,"prefix":"","firstName":"Qiang","middleName":"","lastName":"Liu","suffix":""},{"id":444951491,"identity":"47a692eb-2909-4dc3-a288-caf4da2ff5a2","order_by":11,"name":"Fuping You","email":"","orcid":"https://orcid.org/0000-0002-7444-729X","institution":"Peking University Health Science Center","correspondingAuthor":false,"prefix":"","firstName":"Fuping","middleName":"","lastName":"You","suffix":""}],"badges":[],"createdAt":"2025-04-18 05:45:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6476256/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6476256/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":81233778,"identity":"4be27c74-0d69-488b-beb8-8a0dce25d4b2","added_by":"auto","created_at":"2025-04-23 18:39:35","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":27419290,"visible":true,"origin":"","legend":"Article File","description":"","filename":"Co68manuscriptFigures.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6476256/v1_covered_e22d9533-f971-4c08-8c10-c571e162f2f2.pdf"},{"id":81015270,"identity":"6420e98b-2e78-4404-9056-3bfe195ea25c","added_by":"auto","created_at":"2025-04-21 08:50:18","extension":"zip","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":17131,"visible":true,"origin":"","legend":"Supplementary Materials","description":"","filename":"SupplementaryMaterials.zip","url":"https://assets-eu.researchsquare.com/files/rs-6476256/v1/d7d7225fa048a363a260e6c4.zip"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"\u003cp\u003ePhosphines-Nitrogen-Phosphines chelated CoCl\u003csub\u003e2\u003c/sub\u003e is a novel therapeutic agent for pancreatic cancer\u003c/p\u003e","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Pancreatic ductal adenocarcinoma (PDAC), Inflammatory response, Innate immunity response, Convolutional neural network, Phosphines-Nitrogen-Phosphines (PNP)-pincer ligands, TLR4, STAT1, NF-κB","lastPublishedDoi":"10.21203/rs.3.rs-6476256/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6476256/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Pancreatic cancer is projected to become the second leading cause of cancer-related deaths globally by 2030, yet effective therapeutic options remain limited. Within the pancreatic cancer tumor microenvironment (TME), tumor-associated macrophages (TAMs) secrete interleukin-1 beta (IL-1β), promoting cancer progression while suppressing type I interferons (IFN-I), which is critical for tumor killing. Utilizing the convolutional neural network (CNN)-based DLINP model developed in our laboratory, we identified Co68—an effective metal catalyst featuring a Phosphines-Nitrogen-Phosphines (PNP)-chelated CoCl₂ complex—as a promising candidate to modulate innate immune responses. In animal models of pancreatic cancer, Co68 demonstrated superior antitumor efficacy compared to the STING agonist DMXAA and showed enhanced therapeutic effects when combined with PD-1 blockade. Single-cell RNA sequencing (scRNA-seq) revealed that Co68 reprogramed TAMs to express interferon-stimulated genes (ISGs), attenuated pro-inflammatory cytokine secretion, and disrupted the IL-1β-PGE2 feedback loop, thereby facilitating the recruitment of NK and cytotoxic CD8+ T cells into the TME. Mechanistically, Co68 activated the IFN-I signaling pathway through the TLR4-TRIF-IFN-I axis and inhibited inflammation via the TLR4-SYK-STAT1 pathway. Collectively, these findings highlight the therapeutic potential of Co68, derived from PNP-pincer chemistry, to reshape immune dynamics within the pancreatic cancer TME, positioning it as a promising candidate for innovative immunotherapy strategies.","manuscriptTitle":"Phosphines-Nitrogen-Phosphines chelated CoCl2 is a novel therapeutic agent for pancreatic cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-21 08:50:14","doi":"10.21203/rs.3.rs-6476256/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5a2404fe-c661-4e96-9402-44dd92fb297b","owner":[],"postedDate":"April 21st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":47437973,"name":"Biological sciences/Immunology/Innate immunity/Pattern recognition receptors/Toll-like receptors"},{"id":47437974,"name":"Biological sciences/Drug discovery/Drug screening/High-throughput screening"},{"id":47437975,"name":"Biological sciences/Immunology/Immune evasion"},{"id":47437976,"name":"Biological sciences/Cancer/Cancer microenvironment"},{"id":47437977,"name":"Biological sciences/Cancer/Cancer therapy/Cancer immunotherapy"}],"tags":[],"updatedAt":"2025-04-23T18:30:23+00:00","versionOfRecord":[],"versionCreatedAt":"2025-04-21 08:50:14","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6476256","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6476256","identity":"rs-6476256","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}