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Eukaryotic chromosomes possess specialized telomere structures to maintain genomic stability. In most proliferative cells, telomerase adds telomeric repeats during S\u2010phase. In differentiated cells where telomerase is silenced, telomeres shorten progressively, thereby compromising genomic integrity. Consequently, cancer cells universally activate alternative telomere maintenance mechanisms during malignant transformation: ~80% reactivate telomerase, while a portion of the rest rely on BIR (break\u2010induced replication)\u2013mediated homologous recombination\u2010based ALT (alternative lengthening of telomeres). Although these mechanisms are stable once established, the initial determinants influencing a cancer cell's choice remain poorly understood. This review discusses recent molecular insights into how telomeric chromatin properties profoundly impact this choice. After briefly introducing telomere chromatin characteristics and key players in its maintenance and dynamics, we discuss the mechanisms by which cancer cells acquire distinct telomere replication capabilities. In particular, we present an in\u2010depth analysis linking telomere heterochromatin status to ALT. Furthermore, based on recent advances, we propose a coupled feedforward loop model explaining how the ALT state becomes \u201clocked in\u201d once initiated. Finally, we offer novel perspectives on rational, telomere\u2010centric therapeutic interventions for ALT\u2010positive cancers, focusing on strategies designed to disrupt such feedforward loops by manipulating telomeric chromatin structure.<\/jats:p>","DOI":"10.1111\/acel.70694","type":"journal-article","created":{"date-parts":[[2026,9,6]],"date-time":"2026-09-06T14:58:06Z","timestamp":1788706686000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Twisting the End Game: How Telomere Chromatin Modifications Shape Telomere Maintenance"],"prefix":"10.1111","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6901-334X","authenticated-orcid":false,"given":"Jie","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Ophthalmology The First Affiliated Hospital of Zhengzhou University  Zhengzhou Henan China"},{"name":"Sanmenxia Central Hospital Henan University of Science and Technology  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