{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T15:26:09Z","timestamp":1787325969980,"version":"build-2736575974"},"reference-count":151,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T00:00:00Z","timestamp":1787270400000},"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>Philadelphia-negative (Ph-negative) myeloproliferative neoplasms (MPNs) include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), which are clonal hematopoietic disorders caused by somatic gene mutations in the JAK2, CALR, or MPL genes. Mutations activate the JAK\u2013STAT pathway and disrupt NF-\u03baB signaling, leading to a chronic inflammatory state caused by pro-inflammatory cytokines and reactive oxygen species (ROS). This altered microenvironment causes serious clinical features of the disease, such as bone marrow fibrosis, splenomegaly, vascular niche remodeling, and a greater probability of thrombosis or secondary leukemic transformation. Concurrently, MPNs cause both severe immune dysregulation and tumor evasion, as evidenced by progressive lymphopenia, T and B cell exhaustion, Natural Killer cell maturation arrest, and the accumulation of myeloid-derived suppressor cells. Although FDA-approved JAK1\/JAK2 inhibitors ruxolitinib, fedratinib pacritinib and momelotinib effectively reduce splenomegaly and symptom burden and have demonstrated survival benefits in clinical trials, their ability to eliminate malignant clones or induce durable disease modification remains limited, and disease progression continues to occur in most patients. Finally, this review assesses the complex immunological dysfunction and chronic inflammatory dysregulation that characterize Ph-negative MPNs, as well as emerging therapeutic strategies, emphasizing the importance of fully understanding these intricate microenvironmental mechanisms for the identification and development of novel precision treatment targets.<\/jats:p>","DOI":"10.3390\/cancers18162718","type":"journal-article","created":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T14:20:36Z","timestamp":1787322036000},"page":"2718","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Inflammatory and Immune Microenvironment in Myeloproliferative Neoplasms: Pathogenic Mechanisms and Therapeutic Opportunities"],"prefix":"10.3390","volume":"18","author":[{"given":"Faride","family":"Kaikavoosnejad","sequence":"first","affiliation":[{"name":"Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran, 8715988141"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"Keyhani","sequence":"additional","affiliation":[{"name":"Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran, 8715988141"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seyyede Sepide","family":"Ashraf Moosavi","sequence":"additional","affiliation":[{"name":"Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran, 8715988141"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milad","family":"Verdi","sequence":"additional","affiliation":[{"name":"Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran, 8715988141"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-0854-3172","authenticated-orcid":false,"given":"Mohammad Sepehr","family":"Yazdani","sequence":"additional","affiliation":[{"name":"Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran, 8715988141"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khadijeh","family":"Dizaji Asl","sequence":"additional","affiliation":[{"name":"Department of Histopathology and Anatomy, TaMS.C., Islamic Azad University, Tabriz, Iran, 5157944533"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeinab","family":"Mazloumi","sequence":"additional","affiliation":[{"name":"Department of Medical Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran, 5166614711"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hamed","family":"Mirzaei","sequence":"additional","affiliation":[{"name":"Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran, 8715988141"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5594-2906","authenticated-orcid":false,"given":"Ali","family":"Rafat","sequence":"additional","affiliation":[{"name":"Anatomical Sciences Research Center, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran, 8715988141"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2188-156X","authenticated-orcid":false,"given":"Reza","family":"Nejati","sequence":"additional","affiliation":[{"name":"Department of Pathology, Fox Chase Cancer Center, Temple University Health System, Philadelphia, PA 19111, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,21]]},"reference":[{"key":"ref_1","unstructured":"Thapa, B., Fazal, S., Parsi, M., and Rogers, H.J. 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