{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T21:24:52Z","timestamp":1791494692809,"version":"4.3.4"},"reference-count":119,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T00:00:00Z","timestamp":1769040000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Hematologic malignancies, including chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), non-Hodgkin lymphoma (NHL), and multiple myeloma (MM), are characterized by high relapse rates due to intrinsic and acquired drug resistance. Resistance mechanisms often involve dysregulation of apoptosis pathways, such as B-cell lymphoma 2 (BCL2) family overexpression, and immune evasion through microenvironment modulation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Purpose<\/jats:title>\n                    <jats:p>This review synthesizes recent advances (2020\u20132025) in therapeutic strategies targeting these mechanisms, focusing on BCL2 inhibition and immunomodulatory approaches to overcome resistance and improve outcomes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We systematically reviewed literature from PubMed, Nature, and other databases, emphasizing clinical trials, mechanistic studies, and emerging combinations published between 2020 and 2025. Main Findings: BCL2 inhibitors like venetoclax have achieved high response rates (ORR &amp;gt;70%) in CLL and AML but face resistance\n                      <jats:italic>via<\/jats:italic>\n                      MCL1\/BCL-XL upregulation. Next-generation agents (e.g., sonrotoclax) and combinations address this. Immunomodulatory therapies, including immunomodulatory imide drugs (IMiDs) and chimeric antigen receptor T-Cell immunotherapy (CAR-T cells), enhance T\/NK cell activity, with objective response rate (ORR) up to 90% in relapsed MM. Integrated strategies combining BCL2 inhibition with immunotherapy show synergistic effects, improving progression-free survival (PFS) by 30%\u201340%.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These strategies represent a paradigm shift toward precision medicine, but challenges like toxicity and biomarker-driven resistance persist. Future directions include AI-guided predictions and novel degraders like proteolysis-targeting chimeras (PROTACs).<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2025.1742651","type":"journal-article","created":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T14:15:42Z","timestamp":1769091342000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Novel therapeutic strategies targeting resistance mechanisms in hematologic malignancies: from BCL2 inhibition to immunomodulatory approaches"],"prefix":"10.3389","volume":"16","author":[{"given":"Qianyu","family":"Han","sequence":"first","affiliation":[{"name":"Department of Thoracic Surgery, The Second Affiliated Hospital of Naval Medical University (Changzheng Hospital)","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shasha","family":"Jiang","sequence":"additional","affiliation":[{"name":"The 990th Hospital of the Jointservice Support Force of the PLA","place":["Zhumadian, Henan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jirui","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, The Second Affiliated Hospital of Naval Medical University (Changzheng Hospital)","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Xue","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, The Second Affiliated Hospital of Naval Medical University (Changzheng Hospital)","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2385","DOI":"10.1158\/1078-0432.CCR-22-3321","article-title":"Novel BCL-2 inhibitor lisaftoclax in relapsed or refractory chronic lymphocytic leukemia and other hematologic malignancies: First-in-human open-label trial","volume":"29","author":"Ailawadhi","year":"2023","journal-title":"Clin. 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