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Epigenetic mechanisms are implicated in enabling the acquisition of new phenotypic traits as drivers of colorectal cancer progression, rather than new genetic mutations or expansion of existing mutant clones. It remains unclear, however, which epigenetic mechanisms sustain colorectal cancer plasticity, how they are induced, and how this plasticity generates subclonal diversity that drives the aggressive cancer phenotype. Here we identify the integrated stress response as an inducer of colorectal cancer cell plasticity, subclonal diversity, and tumor progression in the stress-surviving cells. Combined analysis of chromatin accessibility and gene transcription profiling in these cells found the emergence of an endogenous interferon response as a key phenotypic trait associated with subclonal colorectal cancer cell diversity, treatment resistance and heightened aggressiveness. We unveil a new experimental approach to successfully prevent treatment-resistant colorectal cancer progression by combining epigenetic modulators with a cereblon-dependent degrader of GSPT1, a regulator of protein synthesis, to normalize chromatin accessibility and induce colorectal cancer cell death. Collectively, our study identifies the integrated stress response as an inducer of epigenetic and transcriptional plasticity in colorectal cancer cells and highlights a successful approach to therapeutic intervention.<\/jats:p>","DOI":"10.1038\/s41419-026-08720-2","type":"journal-article","created":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T10:37:10Z","timestamp":1775817430000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Targeting the epigenome and the integrated stress response to normalize colorectal cancer subclonal plasticity and progression"],"prefix":"10.1038","volume":"17","author":[{"given":"Lili","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taekyu","family":"Ha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0677-2792","authenticated-orcid":false,"given":"Jing-Xin","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"DiPrima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dunrui","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2943-801X","authenticated-orcid":false,"given":"Parthav","family":"Jailwala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7185-5597","authenticated-orcid":false,"given":"Thomas","family":"Meyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin","family":"Lack","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hidetaka","family":"Ohnuki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1663-3227","authenticated-orcid":false,"given":"Giovanna","family":"Tosato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,10]]},"reference":[{"key":"8720_CR1","doi-asserted-by":"publisher","first-page":"1065","DOI":"10.1016\/S1470-2045(14)70330-4","volume":"15","author":"V Heinemann","year":"2014","unstructured":"Heinemann V, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran SE, et al. 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G.T. reports research support from Celgene (now Bristol Myers Squibb) and Amgen; and is a coinventor on patents or patent applications related to internalization of target receptors, epigenetic analysis, and ephrin tyrosine kinase inhibitors. All rights, title, and interest to these patents have been assigned to the US Department of Health and Human Services. No other disclosures by the Authors.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"All animal experiments were approved by the Institutional Animal Care and Use Committee of the Center for Cancer Research (CCR, Bethesda, MD), NCI, NIH, and were conducted according to the NIH Guide for the Care and Use of Laboratory Animals (National Academies Press, 2011).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics statement"}}],"article-number":"459"}}