{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T10:29:36Z","timestamp":1785407376670,"version":"3.56.0"},"posted":{"date-parts":[[2026,5,14]]},"group-title":"Synthetic Biology","reference-count":71,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T00:00:00Z","timestamp":1778716800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["R01GM118384"],"award-info":[{"award-number":["R01GM118384"]}],"id":[{"id":"https:\/\/ror.org\/04q48ey07","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01CA258300"],"award-info":[{"award-number":["R01CA258300"]}],"id":[{"id":"https:\/\/ror.org\/040gcmg81","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,14]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Protein immunotherapies can elicit potent tumor rejection, but reversible target engagement, incomplete tumor retention, and systemic leakage often erode spatial control. Here, we develop covalently anchored tumor immunotherapeutic proteins (CATIPs), a modular platform that uses proximity-enabled covalent chemistry to immobilize immune cues on tumor-cell surfaces after intratumoral administration. CATIPs combine tumor-targeting nanobodies with payloads for T cell engagement, co-stimulation, and cytokine support. In human PBMC-reconstituted NSG mice, CATIPs completely eradicated treated EGFR-positive tumors, outperforming matched non-covalent proteins while limiting redistribution, systemic T cell activation, cytokine release, xGVHD-associated morbidity, and on-target, off tumor toxicity. In immunocompetent melanoma models, CATIPs remodeled the tumor microenvironment, expanded antigen-specific CD8\n                  <jats:sup>+<\/jats:sup>\n                  T cells, induced antigen-restricted abscopal control, and generated durable protection against local and metastatic rechallenge. CATIP-engineered tumor cells further functioned as whole-cell vaccines. Thus, covalent tumor anchoring converts local protein delivery into tumor-surface immune programming, enabling systemic, tumor-specific, durable antitumor immunity while limiting systemic immunopathology.\n                <\/jats:p>","DOI":"10.64898\/2026.05.13.724746","type":"posted-content","created":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T04:00:18Z","timestamp":1778817618000},"source":"Crossref","is-referenced-by-count":0,"title":["Covalent tumor anchoring spatially orchestrates antitumor immunity"],"prefix":"10.64898","author":[{"given":"Qingke","family":"Li","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry, the Cardiovascular Research Institute, and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongfei","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, the Cardiovascular Research Institute, and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, the Cardiovascular Research Institute, and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, the Cardiovascular Research Institute, and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingchen","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, the Cardiovascular Research Institute, and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5859-2526","authenticated-orcid":false,"given":"Lei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, the Cardiovascular Research Institute, and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026051817402172000_2026.05.13.724746v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-024-00699-2"},{"key":"2026051817402172000_2026.05.13.724746v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-020-0306-5"},{"key":"2026051817402172000_2026.05.13.724746v1.3","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-023-00789-4"},{"key":"2026051817402172000_2026.05.13.724746v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-023-00884-8"},{"key":"2026051817402172000_2026.05.13.724746v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-025-01229-3"},{"key":"2026051817402172000_2026.05.13.724746v1.6","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-024-00903-0"},{"key":"2026051817402172000_2026.05.13.724746v1.7","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-024-00896-6"},{"key":"2026051817402172000_2026.05.13.724746v1.8","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1703481"},{"key":"2026051817402172000_2026.05.13.724746v1.9","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-022-00557-6"},{"key":"2026051817402172000_2026.05.13.724746v1.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2026.03.011"},{"key":"2026051817402172000_2026.05.13.724746v1.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.03.006"},{"key":"2026051817402172000_2026.05.13.724746v1.12","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-024-01111-8"},{"key":"2026051817402172000_2026.05.13.724746v1.13","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-021-00507-y"},{"key":"2026051817402172000_2026.05.13.724746v1.14","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-026-10341-w"},{"key":"2026051817402172000_2026.05.13.724746v1.15","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aaw2614"},{"key":"2026051817402172000_2026.05.13.724746v1.16","doi-asserted-by":"publisher","DOI":"10.1038\/s41551-021-00831-9"},{"key":"2026051817402172000_2026.05.13.724746v1.17","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-024-01925-7"},{"key":"2026051817402172000_2026.05.13.724746v1.18","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2023.09.009"},{"key":"2026051817402172000_2026.05.13.724746v1.19","doi-asserted-by":"publisher","DOI":"10.1038\/nrd.2018.75"},{"key":"2026051817402172000_2026.05.13.724746v1.20","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-021-00363-z"},{"key":"2026051817402172000_2026.05.13.724746v1.21","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aau3259"},{"key":"2026051817402172000_2026.05.13.724746v1.22","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-27390-6"},{"key":"2026051817402172000_2026.05.13.724746v1.23","doi-asserted-by":"publisher","DOI":"10.1038\/s44222-023-00030-y"},{"key":"2026051817402172000_2026.05.13.724746v1.24","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-023-00536-9"},{"key":"2026051817402172000_2026.05.13.724746v1.25","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-025-09212-7"},{"key":"2026051817402172000_2026.05.13.724746v1.26","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.05.028"},{"key":"2026051817402172000_2026.05.13.724746v1.27","doi-asserted-by":"publisher","DOI":"10.1016\/j.chempr.2022.07.012"},{"key":"2026051817402172000_2026.05.13.724746v1.28","doi-asserted-by":"publisher","DOI":"10.1021\/acscentsci.3c00288"},{"key":"2026051817402172000_2026.05.13.724746v1.29","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.add4817"},{"key":"2026051817402172000_2026.05.13.724746v1.30","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-21-0502"},{"key":"2026051817402172000_2026.05.13.724746v1.31","doi-asserted-by":"publisher","DOI":"10.1126\/science.adn9083"},{"key":"2026051817402172000_2026.05.13.724746v1.32","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.8b01087"},{"key":"2026051817402172000_2026.05.13.724746v1.33","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-020-00322-0"},{"key":"2026051817402172000_2026.05.13.724746v1.34","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202412843"},{"key":"2026051817402172000_2026.05.13.724746v1.35","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-17-0310"},{"key":"2026051817402172000_2026.05.13.724746v1.36","doi-asserted-by":"publisher","DOI":"10.1002\/eji.202350773"},{"key":"2026051817402172000_2026.05.13.724746v1.37","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-024-01061-1"},{"key":"2026051817402172000_2026.05.13.724746v1.38","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-29286-5"},{"key":"2026051817402172000_2026.05.13.724746v1.39","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0830-7"},{"key":"2026051817402172000_2026.05.13.724746v1.40","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abo0205"},{"key":"2026051817402172000_2026.05.13.724746v1.41","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202300040R"},{"key":"2026051817402172000_2026.05.13.724746v1.42","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202001203R"},{"key":"2026051817402172000_2026.05.13.724746v1.43","doi-asserted-by":"publisher","DOI":"10.1080\/19420862.2023.2220839"},{"key":"2026051817402172000_2026.05.13.724746v1.44","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-022-00721-2"},{"key":"2026051817402172000_2026.05.13.724746v1.45","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01943"},{"key":"2026051817402172000_2026.05.13.724746v1.46","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0407359101"},{"key":"2026051817402172000_2026.05.13.724746v1.47","doi-asserted-by":"publisher","DOI":"10.1038\/nrd4296"},{"key":"2026051817402172000_2026.05.13.724746v1.48","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.adx1582"},{"key":"2026051817402172000_2026.05.13.724746v1.49","doi-asserted-by":"publisher","DOI":"10.1126\/science.adx9954"},{"key":"2026051817402172000_2026.05.13.724746v1.50","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aan4488"},{"key":"2026051817402172000_2026.05.13.724746v1.51","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05192-0"},{"key":"2026051817402172000_2026.05.13.724746v1.52","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-025-01208-8"},{"key":"2026051817402172000_2026.05.13.724746v1.53","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2025.12.026"},{"key":"2026051817402172000_2026.05.13.724746v1.54","doi-asserted-by":"publisher","DOI":"10.1080\/14740338.2021.1915279"},{"key":"2026051817402172000_2026.05.13.724746v1.55","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2014.57.4756"},{"key":"2026051817402172000_2026.05.13.724746v1.56","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-024-01081-5"},{"key":"2026051817402172000_2026.05.13.724746v1.57","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-025-00893-w"},{"key":"2026051817402172000_2026.05.13.724746v1.58","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-020-0376-4"},{"key":"2026051817402172000_2026.05.13.724746v1.59","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-022-00732-1"},{"key":"2026051817402172000_2026.05.13.724746v1.60","doi-asserted-by":"publisher","DOI":"10.1126\/science.abq7248"},{"key":"2026051817402172000_2026.05.13.724746v1.61","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-020-0345-y"},{"key":"2026051817402172000_2026.05.13.724746v1.62","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-022-00722-1"},{"key":"2026051817402172000_2026.05.13.724746v1.63","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-026-01296-0"},{"key":"2026051817402172000_2026.05.13.724746v1.64","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2425781122"},{"key":"2026051817402172000_2026.05.13.724746v1.65","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.83659"},{"key":"2026051817402172000_2026.05.13.724746v1.66","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2024.03.037"},{"key":"2026051817402172000_2026.05.13.724746v1.67","doi-asserted-by":"publisher","DOI":"10.1038\/nri3862"},{"key":"2026051817402172000_2026.05.13.724746v1.68","doi-asserted-by":"publisher","DOI":"10.65641\/afmnai-2025-159"},{"key":"2026051817402172000_2026.05.13.724746v1.69","doi-asserted-by":"publisher","DOI":"10.1038\/s41551-025-01492-8"},{"key":"2026051817402172000_2026.05.13.724746v1.70","doi-asserted-by":"publisher","DOI":"10.1038\/nrd.2018.169"},{"key":"2026051817402172000_2026.05.13.724746v1.71","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2025.10.030"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.05.13.724746","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T00:40:27Z","timestamp":1779151227000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.05.13.724746"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,14]]},"references-count":71,"URL":"https:\/\/doi.org\/10.64898\/2026.05.13.724746","relation":{},"subject":[],"published":{"date-parts":[[2026,5,14]]},"subtype":"preprint"}}