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Cancer-associated O-glycans include both truncated structures that are unique to mucin-type O-glycosylation and more elongated terminal motifs that function as ligands for glycan-binding proteins. Instead of representing a simple binary change from elongated to truncated structures, it is increasingly understood that these glycans decorate the cancer cell surface with a heterogeneous pattern of truncated, elongated, capped, and partially processed glycoforms, which coexist even on individual proteins and within the tumor glycocalyx. Functionally, truncated aberrant O-GalNAc glycans, such as Tn, STn, and T perturb epithelial differentiation, barrier integrity, signaling, and immunosuppression through interactions with glycan binding receptors, such as Siglecs and MGL. In addition, more elongated O-glycans, including Lewis antigens, interact with selectins promoting metastasis and cellular trafficking. Moreover, individual GalNAc-transferase isoenzymes, governing site-specific O-glycosylation, are emerging as context-dependent regulators of oncogenic processes through glycosylation of selected proteins. These observations establish cancer-associated O-glycans as context-dependent molecular drivers of tumor progression and promising therapeutic entry points. In this review, we discuss the expression, regulation, and functions of cancer-associated O-glycans, their roles in glycan-binding protein biology, and emerging therapeutic strategies that may enable a new generation of glycan-directed precision treatments in oncology.<\/jats:p>","DOI":"10.1021\/acs.chemrev.5c00901","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T14:39:44Z","timestamp":1785854384000},"page":"8957-9005","source":"Crossref","is-referenced-by-count":0,"title":["From Glycocode\nto Precision Oncology: Therapeutic\nStrategies Targeting Aberrant\n                    <i>O<\/i>\n                    -GalNAc Glycosylation\nin Cancer"],"prefix":"10.1021","volume":"126","author":[{"given":"Mikkel Koed M\u00f8ller","family":"Aasted","sequence":"first","affiliation":[{"name":"University of Copenhagen , , Blegdamsvej 3B , ,","place":["Copenhagen, Denmark, 2200"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thapakorn","family":"Jaroentomeechai","sequence":"additional","affiliation":[{"name":"University of Copenhagen , , Blegdamsvej 3B , ,","place":["Copenhagen, Denmark, 2200"]},{"name":"Mahidol University , , 272 Rama VI Road , , ,","place":["Ratchathewi District, Bangkok, Thailand, 10400"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sally","family":"Dabelsteen","sequence":"additional","affiliation":[{"name":"University of Copenhagen , , Blegdamsvej 3B , ,","place":["Copenhagen, Denmark, 2200"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiren","family":"Joshi","sequence":"additional","affiliation":[{"name":"University of Copenhagen , , Blegdamsvej 3B , ,","place":["Copenhagen, Denmark, 2200"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean R.","family":"Stowell","sequence":"additional","affiliation":[{"name":"Brigham and Women\u2019s Hospital , , 75 Francis Street , , ,","place":["Boston, Massachusetts, United States, 02115"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0240-9232","authenticated-orcid":true,"given":"Hans H.","family":"Wandall","sequence":"additional","affiliation":[{"name":"University of Copenhagen , , Blegdamsvej 3B , ,","place":["Copenhagen, Denmark, 2200"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"issue":"1","key":"2026090104161434900_cit1","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1146\/annurev-biochem-030122-044347","article-title":"Reading and Writing the Human Glycocode","volume":"93","author":"de Haan","year":"2024","journal-title":"Annu. 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