{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T19:42:41Z","timestamp":1787773361561,"version":"build-2784847793"},"reference-count":195,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T00:00:00Z","timestamp":1768521600000},"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>Mutations in TP53 inhibit p53 protective behaviors including cell cycle arrest, DNA damage repair protein recruitment, and apoptosis. The ubiquity of p53 in genome-stabilizing functions leads to an aberrant tumor microenvironment in TP53-mutated myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Profound immunosuppression mediated by myeloid-derived suppressor cells, the upregulation of cytokines and cell-surface receptors on leukemic cells, the suppression of native immune regulator cells, and metabolic aberrations in the bone marrow are features of the TP53-mutated AML\/MDS marrow microenvironment. These localized changes in the bone marrow microenvironment (BMME) explain why traditional therapies for MDS\/AML, including chemotherapeutics and hypomethylating agents, are not as effective in TP53-mutated myeloid neoplasms and demonstrate the dire need for new treatments in this patient population. The unique pathophysiology of TP53-mutated disease also provides new therapeutic approaches which are being studied, including intracellular targets (MDM2, p53), cell-surface protein biologics (immune checkpoint inhibitors, BiTE therapy, and antibody\u2013drug conjugates), cell therapies (CAR-T, NK-cell), signal transduction pathways (Hedgehog, Wnt, NF-\u03baB, CCRL2, and HIF-1\u03b1), and co-opted biologic pathways (cholesterol synthesis and glycolysis). In this review, we will discuss the pathophysiologic anomalies of the tumor microenvironment in TP53-mutant MDS\/AML, the hypothesized mechanisms of chemoresistance it imparts, and how novel therapies are leveraging diverse therapeutic targets to address this critical area of need.<\/jats:p>","DOI":"10.3390\/cancers18020275","type":"journal-article","created":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T08:08:21Z","timestamp":1768550901000},"page":"275","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Marrow Microenvironmental Pathobiology and Therapeutic Opportunities for TP53-Mutated Myelodysplastic Syndrome\/Acute Myeloid Leukemia"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7552-7980","authenticated-orcid":false,"given":"Cameron J.","family":"Hunter","sequence":"first","affiliation":[{"name":"Division of Malignant Hematology and Medical Oncology, Department of Medicine, UPMC Hillman Cancer Center, Pittsburgh, PA 15232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annie P.","family":"Im","sequence":"additional","affiliation":[{"name":"Division of Malignant Hematology and Medical Oncology, Department of Medicine, UPMC Hillman Cancer Center, Pittsburgh, PA 15232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rory M.","family":"Shallis","sequence":"additional","affiliation":[{"name":"Department of Malignant Hematology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"188556","DOI":"10.1016\/j.bbcan.2021.188556","article-title":"Tumor suppressor p53: Biology, signaling pathways, and therapeutic targeting","volume":"1876","year":"2021","journal-title":"Biochim. Biophys. Acta (BBA) Rev. Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1038\/358015a0","article-title":"Cancer. p53, guardian of the genome","volume":"358","author":"Lane","year":"1992","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1016\/j.molcel.2017.05.015","article-title":"ATM, ATR, and DNA-PK: The Trinity at the Heart of the DNA Damage Response","volume":"66","author":"Blackford","year":"2017","journal-title":"Mol. 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