Integrative Multi-omics Guides PD-1 Blockade Therapy in the Rare and Aggressive Colorectal Adenosquamous Carcinoma

Integrative Multi-omics Guides PD-1 Blockade Therapy in the Rare and Aggressive Colorectal Adenosquamous Carcinoma | 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 Integrative Multi-omics Guides PD-1 Blockade Therapy in the Rare and Aggressive Colorectal Adenosquamous Carcinoma Jun Huang, Yandong Zhao, Qijun Yao, Zhongcheng Liu, Fengyun Pei, and 27 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8826108/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Colorectal adenosquamous carcinoma (CRASC) is a rare and aggressive malignancy without standardized treatment, posing a grave clinical challenge. Here, we performed integrative multi-omics analysis on the largest multicenter cohort to date, to delineate its molecular and spatial architecture. Whole-exome sequencing showed that adenocarcinoma (AC) and squamous cell carcinoma (SCC) components originate from a common ancestral clone, followed by lineage specific divergence, establishing CRASC as a unified evolutionary entity. Spatially resolved transcriptomics uncovers a compartmentalized ecosystem. SCC enriched regions were embedded in a fibroblast dense, metabolically active, and immune restrictive stroma, whereas AC niches form immunogenic hubs with enhanced antigen presentation and cytotoxic T cell engagement. Clinically, we provided proof-of-concept evidence that CRASC patients can achieve sustained progression-free survival following immunotherapy-based regimens in both adjuvant and neoadjuvant settings. Our findings redefine CRASC as a spatially organized, evolutionarily unified malignancy and establish spatial lineage architecture as a biomarker for CRASC immunotherapy selection. Health sciences/Oncology/Cancer/Cancer microenvironment Biological sciences/Cancer/Gastrointestinal cancer/Colorectal cancer Biological sciences/Cancer/Cancer therapy/Cancer immunotherapy Health sciences/Oncology/Cancer/Tumour biomarkers Health sciences/Diseases/Cancer/Gastrointestinal cancer/Colorectal cancer Colorectal adenosquamous carcinoma Multi-omics profiling Tumor microenvironment Immunotherapy Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementaryTable1.docx Supplementary Table 1 ExtendedDataFig.16.pdf Extended Data Fig.1-6 nrreportingsummary.pdf nr-reporting-summary Cite Share Download PDF Status: Under Review 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-8826108","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":594637846,"identity":"8cf51983-6d4f-4c56-8bf7-b60ad5e86237","order_by":0,"name":"Jun Huang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABEklEQVRIiWNgGAWjYBACAzDJY1PfD6QOPIAJ8xDWksY4swGoJYF4LQyHGTccAFJEaTGXSH728IvMYWbja4cfAm2pS5w/I4Hxwds2BnlzHFosZ6SZG8vwpLOZ3U4zAGo5nLjhRgKz4dw2BsOdDTgcdiPBTFqCx5rH7HYCSMuBxA0SCWzSvG0MQC4uLenfgFqYJYxnp3+AOYz9N34tOWaSH3icDQykc0C2MCc23EhgY8ar5cybMmlgICdI3M4pOJBgcNh4w5mHzZJzzkkYbsCl5Xj6NsmfPTYJ/LPTN3/4UFEnO789+eCHN2U28rhsAQFm3h64CQyODQyMDUCWBG71QMD44weCY49X6SgYBaNgFIxIAAAfMl+BOiKoEgAAAABJRU5ErkJggg==","orcid":"","institution":"Sun Yat-sen University","correspondingAuthor":true,"prefix":"","firstName":"Jun","middleName":"","lastName":"Huang","suffix":""},{"id":594637847,"identity":"b010ce50-3625-4dea-96b7-04cdb03c60c7","order_by":1,"name":"Yandong Zhao","email":"","orcid":"","institution":"Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Yandong","middleName":"","lastName":"Zhao","suffix":""},{"id":594637848,"identity":"b13294e4-1ffd-42dd-8e05-55b905daa34b","order_by":2,"name":"Qijun Yao","email":"","orcid":"","institution":"Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Qijun","middleName":"","lastName":"Yao","suffix":""},{"id":594637849,"identity":"2816a5e0-7bc0-40b3-bc6f-de23314d6526","order_by":3,"name":"Zhongcheng Liu","email":"","orcid":"","institution":"Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Zhongcheng","middleName":"","lastName":"Liu","suffix":""},{"id":594637850,"identity":"690ed419-c552-49db-9a42-aa5ccba3c8a0","order_by":4,"name":"Fengyun Pei","email":"","orcid":"","institution":"Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Fengyun","middleName":"","lastName":"Pei","suffix":""},{"id":594637851,"identity":"3f044f54-a595-4ad6-9077-e0c6018f3015","order_by":5,"name":"Lingyu Han","email":"","orcid":"","institution":"1.Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China; 2.Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.","correspondingAuthor":false,"prefix":"","firstName":"Lingyu","middleName":"","lastName":"Han","suffix":""},{"id":594637852,"identity":"f0c53304-1331-48fd-a408-01b9825094d0","order_by":6,"name":"Chao Zhang","email":"","orcid":"","institution":"State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou 510060","correspondingAuthor":false,"prefix":"","firstName":"Chao","middleName":"","lastName":"Zhang","suffix":""},{"id":594637853,"identity":"0ee1933e-18e0-4ddf-8764-10663a1de5bb","order_by":7,"name":"Haipeng Chen","email":"","orcid":"","institution":"Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":false,"prefix":"","firstName":"Haipeng","middleName":"","lastName":"Chen","suffix":""},{"id":594637854,"identity":"09a9280a-7648-4b3f-9577-6fc289da9978","order_by":8,"name":"Yuan Tang","email":"","orcid":"","institution":"Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":false,"prefix":"","firstName":"Yuan","middleName":"","lastName":"Tang","suffix":""},{"id":594637855,"identity":"53d63883-dc20-488c-8ec1-f56f31f51620","order_by":9,"name":"Guanyu Yu","email":"","orcid":"https://orcid.org/0000-0001-5416-3559","institution":"Changhai Hospital, Naval Medical University","correspondingAuthor":false,"prefix":"","firstName":"Guanyu","middleName":"","lastName":"Yu","suffix":""},{"id":594637856,"identity":"385a04b6-38b6-43ea-ad1d-4ce9c90e1099","order_by":10,"name":"Fang He","email":"","orcid":"","institution":"Sun Yat-Sen University","correspondingAuthor":false,"prefix":"","firstName":"Fang","middleName":"","lastName":"He","suffix":""},{"id":594637857,"identity":"cd4db4f9-6db8-4c65-9d0f-5edc762ee0d0","order_by":11,"name":"Zhimin Liu","email":"","orcid":"","institution":"Sun Yat-Sen University","correspondingAuthor":false,"prefix":"","firstName":"Zhimin","middleName":"","lastName":"Liu","suffix":""},{"id":594637858,"identity":"9e6d9929-ef16-4d70-95ce-f4b23965f67e","order_by":12,"name":"Menghan Wang","email":"","orcid":"","institution":"Sun Yat-Sen University","correspondingAuthor":false,"prefix":"","firstName":"Menghan","middleName":"","lastName":"Wang","suffix":""},{"id":594637859,"identity":"4a9b0c33-c605-4dd0-9d5a-c4b68d8773b6","order_by":13,"name":"Qin Guo","email":"","orcid":"","institution":"Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Qin","middleName":"","lastName":"Guo","suffix":""},{"id":594637860,"identity":"13f42606-0f2a-4c61-b5df-4667e6eb2950","order_by":14,"name":"Lishuo Shi","email":"","orcid":"","institution":"The Sixth Affiliated Hospital, Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Lishuo","middleName":"","lastName":"Shi","suffix":""},{"id":594637861,"identity":"fd918312-ac0b-480c-851d-907c736fb7eb","order_by":15,"name":"Li Ling","email":"","orcid":"","institution":"Department of Medical Statistics, School of Public Health, Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Li","middleName":"","lastName":"Ling","suffix":""},{"id":594637862,"identity":"5f030142-89a4-41d4-8a86-4194a009d3d8","order_by":16,"name":"Yuanzhi Cheng","email":"","orcid":"","institution":"Chengdu BasebioTech Co., Ltd","correspondingAuthor":false,"prefix":"","firstName":"Yuanzhi","middleName":"","lastName":"Cheng","suffix":""},{"id":594637863,"identity":"a7dd8fd4-23e0-45ea-9e01-56dbad263b7c","order_by":17,"name":"Cheng Wang","email":"","orcid":"","institution":"Chengdu BasebioTech Co., Ltd","correspondingAuthor":false,"prefix":"","firstName":"Cheng","middleName":"","lastName":"Wang","suffix":""},{"id":594637864,"identity":"2c93c8f9-bce6-4d55-bf25-c006a2f24e95","order_by":18,"name":"Zezheng Pan","email":"","orcid":"","institution":"LC-Bio Technology (Hangzhou) Co., LTD., Hangzhou, Zhejiang, China","correspondingAuthor":false,"prefix":"","firstName":"Zezheng","middleName":"","lastName":"Pan","suffix":""},{"id":594637865,"identity":"82311d96-628a-4300-a8c6-03ff07059385","order_by":19,"name":"Zhengbiao Zhu","email":"","orcid":"","institution":"LC-Bio Technology (Hangzhou) Co., LTD., Hangzhou, Zhejiang, China","correspondingAuthor":false,"prefix":"","firstName":"Zhengbiao","middleName":"","lastName":"Zhu","suffix":""},{"id":594637866,"identity":"c54eaabe-0b16-4e9f-997b-e8e3ce7f0fc7","order_by":20,"name":"Yan Wang","email":"","orcid":"","institution":"LC-Bio Technology (Hangzhou) Co., LTD., Hangzhou, Zhejiang, China","correspondingAuthor":false,"prefix":"","firstName":"Yan","middleName":"","lastName":"Wang","suffix":""},{"id":594637867,"identity":"664a0c71-e2a9-48d8-98b1-8d864128f1de","order_by":21,"name":"Chunge Zhong","email":"","orcid":"https://orcid.org/0009-0000-7017-7459","institution":"Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, Northeastern University, Shenyang, China","correspondingAuthor":false,"prefix":"","firstName":"Chunge","middleName":"","lastName":"Zhong","suffix":""},{"id":594637868,"identity":"ea9bc6d8-6eb4-47b0-8717-c11bf9584af2","order_by":22,"name":"You Li","email":"","orcid":"","institution":"Key Laboratory of Bioresource Research and Development of Liaoning Province, College of Life and Health Sciences, Northeastern University, Shenyang, China","correspondingAuthor":false,"prefix":"","firstName":"You","middleName":"","lastName":"Li","suffix":""},{"id":594637869,"identity":"6bc192be-d800-40af-abb4-11b96400854f","order_by":23,"name":"Shijia Yan","email":"","orcid":"https://orcid.org/0000-0002-7378-0963","institution":"School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, Guangdong, China","correspondingAuthor":false,"prefix":"","firstName":"Shijia","middleName":"","lastName":"Yan","suffix":""},{"id":594637870,"identity":"2de2f039-1764-4db0-8342-e2b15dd1245f","order_by":24,"name":"Huiya Cheng","email":"","orcid":"","institution":"School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, Guangdong, China","correspondingAuthor":false,"prefix":"","firstName":"Huiya","middleName":"","lastName":"Cheng","suffix":""},{"id":594637871,"identity":"11d18ce1-946e-4384-9e8a-b3abb1a167c0","order_by":25,"name":"Guohui Wan","email":"","orcid":"https://orcid.org/0000-0001-5170-7282","institution":"Sun Yat-sen University","correspondingAuthor":false,"prefix":"","firstName":"Guohui","middleName":"","lastName":"Wan","suffix":""},{"id":594637872,"identity":"97491286-e815-414a-ab1b-605a775002f9","order_by":26,"name":"Teng Fei","email":"","orcid":"https://orcid.org/0000-0001-9620-0450","institution":"Northeastern University","correspondingAuthor":false,"prefix":"","firstName":"Teng","middleName":"","lastName":"Fei","suffix":""},{"id":594637873,"identity":"3e0ea3c8-3f70-42ec-b621-82aed1951d9a","order_by":27,"name":"Zheng Liu","email":"","orcid":"","institution":"GI Cancer Department, Beijing Arion Cancer Center, Beijing, China","correspondingAuthor":false,"prefix":"","firstName":"Zheng","middleName":"","lastName":"Liu","suffix":""},{"id":594637874,"identity":"3f449c2c-ad4c-4041-9a82-27ac1218a6b7","order_by":28,"name":"Hao Wang","email":"","orcid":"","institution":"Shanghai Changhai Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hao","middleName":"","lastName":"Wang","suffix":""},{"id":594637875,"identity":"27e09d83-9f68-47fd-9051-a0361d5ac180","order_by":29,"name":"Ping Liu","email":"","orcid":"","institution":"Department of Colorectal Surgery, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China","correspondingAuthor":false,"prefix":"","firstName":"Ping","middleName":"","lastName":"Liu","suffix":""},{"id":594637876,"identity":"5c14704e-40e6-4eab-80f6-70164d49cc07","order_by":30,"name":"Guoxiang Cai","email":"","orcid":"https://orcid.org/0000-0002-7772-7078","institution":"1.Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China; 2.Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.","correspondingAuthor":false,"prefix":"","firstName":"Guoxiang","middleName":"","lastName":"Cai","suffix":""},{"id":594637877,"identity":"a5f112e3-7875-4eed-bde1-dc62b38b5804","order_by":31,"name":"Rongxin Zhang","email":"","orcid":"https://orcid.org/0000-0001-5498-0428","institution":"University of Pennsylvania","correspondingAuthor":false,"prefix":"","firstName":"Rongxin","middleName":"","lastName":"Zhang","suffix":""}],"badges":[],"createdAt":"2026-02-09 05:35:58","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8826108/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8826108/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":105564852,"identity":"69970b87-c104-4747-a26e-aaecec0a3604","added_by":"auto","created_at":"2026-03-27 12:51:05","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":13170878,"visible":true,"origin":"","legend":"Article File","description":"","filename":"CRASCmanuscript.2026.2.18.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8826108/v1_covered_d4d2678c-cded-4a76-b679-fbe0a9d128a6.pdf"},{"id":105261888,"identity":"776d2689-34ad-4fe5-a92f-c8f38230454b","added_by":"auto","created_at":"2026-03-24 06:32:48","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":18827,"visible":true,"origin":"","legend":"Supplementary Table 1","description":"","filename":"SupplementaryTable1.docx","url":"https://assets-eu.researchsquare.com/files/rs-8826108/v1/538b64c4dc5c1e89597bb248.docx"},{"id":105261889,"identity":"8368399a-2a21-40e5-8f49-bb9233ce3110","added_by":"auto","created_at":"2026-03-24 06:32:48","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":4999822,"visible":true,"origin":"","legend":"Extended Data Fig.1-6","description":"","filename":"ExtendedDataFig.16.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8826108/v1/ed3a37727fd1e414c27c4b2e.pdf"},{"id":105261890,"identity":"75329c2f-c095-4a01-9181-200fbf7753b5","added_by":"auto","created_at":"2026-03-24 06:32:48","extension":"pdf","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":1666201,"visible":true,"origin":"","legend":"nr-reporting-summary","description":"","filename":"nrreportingsummary.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8826108/v1/b03587c2363e20ada49f9084.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Integrative Multi-omics Guides PD-1 Blockade Therapy in the Rare and Aggressive Colorectal Adenosquamous Carcinoma","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"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":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Colorectal adenosquamous carcinoma, Multi-omics profiling, Tumor microenvironment, Immunotherapy","lastPublishedDoi":"10.21203/rs.3.rs-8826108/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8826108/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Colorectal adenosquamous carcinoma (CRASC) is a rare and aggressive malignancy without standardized treatment, posing a grave clinical challenge. Here, we performed integrative multi-omics analysis on the largest multicenter cohort to date, to delineate its molecular and spatial architecture. Whole-exome sequencing showed that adenocarcinoma (AC) and squamous cell carcinoma (SCC) components originate from a common ancestral clone, followed by lineage specific divergence, establishing CRASC as a unified evolutionary entity. Spatially resolved transcriptomics uncovers a compartmentalized ecosystem. SCC enriched regions were embedded in a fibroblast dense, metabolically active, and immune restrictive stroma, whereas AC niches form immunogenic hubs with enhanced antigen presentation and cytotoxic T cell engagement. Clinically, we provided proof-of-concept evidence that CRASC patients can achieve sustained progression-free survival following immunotherapy-based regimens in both adjuvant and neoadjuvant settings. Our findings redefine CRASC as a spatially organized, evolutionarily unified malignancy and establish spatial lineage architecture as a biomarker for CRASC immunotherapy selection.","manuscriptTitle":"Integrative Multi-omics Guides PD-1 Blockade Therapy in the Rare and Aggressive Colorectal Adenosquamous Carcinoma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-24 06:32:38","doi":"10.21203/rs.3.rs-8826108/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"91358214-7487-4e8d-8acc-3c73645529ad","owner":[],"postedDate":"March 24th, 2026","published":true,"recentEditorialEvents":[{"type":"reviewerAgreed","content":"This content is not available.","date":"2026-05-05T11:01:28+00:00","index":2,"fulltext":"This content is not available."}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":63283090,"name":"Health sciences/Oncology/Cancer/Cancer microenvironment"},{"id":63283091,"name":"Biological sciences/Cancer/Gastrointestinal cancer/Colorectal cancer"},{"id":63283092,"name":"Biological sciences/Cancer/Cancer therapy/Cancer immunotherapy"},{"id":63283093,"name":"Health sciences/Oncology/Cancer/Tumour biomarkers"},{"id":63283094,"name":"Health sciences/Diseases/Cancer/Gastrointestinal cancer/Colorectal cancer"}],"tags":[],"updatedAt":"2026-03-24T06:32:38+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-24 06:32:38","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8826108","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8826108","identity":"rs-8826108","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}