{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T21:09:46Z","timestamp":1792184986335,"version":"4.4.0"},"reference-count":218,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T00:00:00Z","timestamp":1765756800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Cancer reversion therapy represents a paradigm shift in oncology, focusing on reprogramming malignant cells to a non-malignant state rather than destroying them. This narrative review synthesizes current evidence, emerging technologies, and future directions in this promising field. Cancer reversion is founded on key biological observations: somatic cell reprogramming, spontaneous cancer regression, and microenvironmental influences on malignant behavior. Current approaches include epigenetic reprogramming using HDAC inhibitors and DNA methyltransferase inhibitors; microenvironmental modulation through extracellular matrix manipulation and vascular normalization; differentiation therapy exemplified by all-trans retinoic acid in acute promyelocytic leukemia; and targeting oncogene addiction as demonstrated in BCR-ABL-driven leukemias. Emerging technologies accelerating progress include single-cell analyses that reveal cancer heterogeneity and cellular state transitions; CRISPR-based approaches enabling precise genetic and epigenetic manipulation; patient-derived organoids that model tumor complexity; and artificial intelligence applications that identify novel reversion-inducing agents. Critical evaluation reveals that many reported \u201creversion\u201d phenomena represent stimulus-dependent plasticity or transient growth arrest rather than stable phenotypic normalization. True cancer reversion requires durable, heritable phenotypic changes that persist after treatment withdrawal, with evidence of epigenetic consolidation and functional restoration. Despite promising advances, significant challenges remain: cancer cell plasticity facilitating therapeutic escape, difficulties in establishing stable reversion states, delivery challenges for solid tumors, and the need for combination approaches to address tumor heterogeneity. Future directions include integrated multi-omics analyses to comprehensively map cellular state transitions, studies of natural regression phenomena to identify reversion mechanisms, advanced nanodelivery systems for targeted therapy, and synthetic biology approaches creating intelligent therapeutic systems. By redirecting rather than destroying cancer cells, reversion therapy offers the potential for reduced toxicity and resistance, potentially transforming cancer from a deadly disease to a manageable condition.<\/jats:p>","DOI":"10.3390\/cimb47121049","type":"journal-article","created":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T15:15:08Z","timestamp":1765811708000},"page":"1049","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Cancer Reversion Therapy: Prospects, Progress and Future Directions"],"prefix":"10.3390","volume":"47","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-5791-301X","authenticated-orcid":false,"given":"Emmanuel O.","family":"Oisakede","sequence":"first","affiliation":[{"name":"Department of Clinical Oncology, Leeds Teaching Hospitals Trust, Leeds LS9 7TF, UK"},{"name":"Department of Health Research, University of Leeds, Leeds LS2 9JT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0188-9836","authenticated-orcid":false,"given":"David B.","family":"Olawade","sequence":"additional","affiliation":[{"name":"Department of Public Health, York St John University, London E14 2BA, UK"},{"name":"Department of Business, Management and Health, School of Health, Sport and Bioscience, University of East London, London E16 2RD, UK"},{"name":"Department of Research and Innovation, Medway NHS Foundation Trust, Gillingham ME7 5NY, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oluwakemi Jumoke","family":"Bello","sequence":"additional","affiliation":[{"name":"The Clinical Research Centre, the London Clinic, 20 Devonshire Place, London W1G 6BW, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claret Chinenyenwa","family":"Analikwu","sequence":"additional","affiliation":[{"name":"Department of Microbiology, University Hospital Southampton NHS Foundation Trust, Hampshire SO16 6YD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eghosasere","family":"Egbon","sequence":"additional","affiliation":[{"name":"Department of Tissue Engineering and Regenerative Medicine, Faculty of Life Science Engineering, FH Technikum, 1200 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6545-3471","authenticated-orcid":false,"given":"Oluwaseun","family":"Fapohunda","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ 85721-0041, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2512-6131","authenticated-orcid":false,"given":"Stergios","family":"Boussios","sequence":"additional","affiliation":[{"name":"Department of Research and Innovation, Medway NHS Foundation Trust, Gillingham ME7 5NY, UK"},{"name":"Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece"},{"name":"Department of Medical Oncology, Ioannina University Hospital, 45500 Ioannina, Greece"},{"name":"Faculty of Medicine, Health and Social Care, Canterbury Christ Church University, Canterbury CT1 1QU, UK"},{"name":"Faculty of Life Sciences & Medicine, School of Cancer & Pharmaceutical Sciences, King\u2019s College London, Strand, London WC2R 2LS, UK"},{"name":"AELIA Organization, 9th Km Thessaloniki\u2014Thermi, 57001 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,15]]},"reference":[{"key":"ref_1","first-page":"106","article-title":"Systemic treatment-induced gastrointestinal toxicity: Incidence, clinical presentation and management","volume":"25","author":"Boussios","year":"2012","journal-title":"Ann. 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