{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T10:08:00Z","timestamp":1789380480308,"version":"build-2803163510"},"reference-count":121,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T00:00:00Z","timestamp":1789257600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Cutaneous T cell lymphoma (CTCL) comprises a heterogeneous group of skin-homing T cell malignancies, with mycosis fungoides (MF) and S\u00e9zary Syndrome representing the most frequent and clinically relevant entities. Their clinical behavior differs substantially: MF often follows an indolent course over years, whereas S\u00e9zary Syndrome is a distinct clinicopathological entity that is typically characterized by erythroderma, a high burden of circulating malignant T cells and frequent lymph node involvement. Early-stage MF can often be controlled with skin-directed therapies, but advanced, relapsed or refractory CTCL remains therapeutically challenging. Established treatments are selected primarily according to disease stage, disease compartment and surface-target expression, whereas most pathway-directed, redox-modulating and apoptosis-sensitizing approaches remain investigational. Increasing evidence indicates that malignant T cells are maintained by an interconnected survival network rather than by a single dominant oncogenic pathway. This network includes constitutive inflammatory signaling, nuclear factor kappa B (NF-\u03baB) activation, apoptosis resistance, altered redox homeostasis, mitochondrial and metabolic adaptation, rat sarcoma viral oncogene homolog (RAS)\/rapidly accelerated fibrosarcoma (RAF)\/mitogen-activated protein kinase kinase (MEK) signaling and epigenetic regulation. These mechanisms cooperate to promote malignant T cell survival, therapy resistance, and disease progression, but they also create opportunities for targeted therapeutic intervention. Particular emphasis is placed on redox-regulated cell death, nuclear factor kappa B (NF-\u03baB)-dependent survival, B-cell lymphoma 2 (BCL-2) family proteins, RAS pathway alterations, epigenetic sensitization and mechanism-informed treatment strategies. Integrating clinicopathological staging with molecular profiling and functional vulnerability screens may support more rational combination therapies and improve patient stratification in CTCL.<\/jats:p>","DOI":"10.3390\/cancers18182956","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T09:34:01Z","timestamp":1789378441000},"page":"2956","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cutaneous T Cell Lymphoma: Targeting the Survival Network in Mycosis Fungoides and S\u00e9zary Syndrome"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-3803-733X","authenticated-orcid":false,"given":"Philipp","family":"Heumann","sequence":"first","affiliation":[{"name":"Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, Immunology, and Infectious Diseases, University Hospital Regensburg, 93053 Regensburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Mehler","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, Immunology, and Infectious Diseases, University Hospital Regensburg, 93053 Regensburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9284-1138","authenticated-orcid":false,"given":"Sara Martina","family":"Steinmann","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, Immunology, and Infectious Diseases, University Hospital Regensburg, 93053 Regensburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan P.","family":"Nicolay","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, University of Heidelberg, 68167 Mannheim, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8520-4568","authenticated-orcid":false,"given":"Martina","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, Immunology, and Infectious Diseases, University Hospital Regensburg, 93053 Regensburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-2897-3447","authenticated-orcid":false,"given":"Karsten","family":"G\u00fclow","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology, Rheumatology, Immunology, and Infectious Diseases, University Hospital Regensburg, 93053 Regensburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1720","DOI":"10.1038\/s41375-022-01620-2","article-title":"The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms","volume":"36","author":"Alaggio","year":"2022","journal-title":"Leukemia"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1182\/blood.2022015851","article-title":"The International Consensus Classification of Mature Lymphoid Neoplasms: A report from the Clinical Advisory Committee","volume":"140","author":"Campo","year":"2022","journal-title":"Blood"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.1182\/blood-2018-11-881268","article-title":"The 2018 update of the WHO-EORTC classification for primary cutaneous lymphomas","volume":"133","author":"Willemze","year":"2019","journal-title":"Blood"},{"key":"ref_4","first-page":"537","article-title":"S2k-Guidelines\u2013Cutaneous lymphomas (ICD10 C82\u2013C86): Update 2021","volume":"20","author":"Dippel","year":"2022","journal-title":"JDDG J. 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