{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T10:31:54Z","timestamp":1786617114272,"version":"build-2736575974"},"reference-count":125,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"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. Genome Ed."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Chimeric antigen receptor T-cell therapy has changed the treatment landscape of relapsed or refractory hematological malignancies, but primary non-response and post-infusion relapse remain frequent clinical problems. In aggressive B-cell lymphomas, acute leukemias, and multiple myeloma, treatment failure is often driven by overlapping mechanisms rather than a single resistance pathway. These include antigen loss or reduced antigen density, impaired immune recognition, defective inflammatory signaling, checkpoint-mediated suppression, metabolic stress, and limited effector-cell persistence within suppressive disease niches.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Main Body<\/jats:title>\n                    <jats:p>Genome engineering has become an important tool for both identifying and addressing these resistance mechanisms. CRISPR-based functional screening, single-cell perturbation approaches, and multi-omics profiling allow immune escape and tumor microenvironment-mediated resistance to be defined more functionally, rather than inferred only from correlative datasets. These insights can inform the design of CAR-T and CAR-NK therapies through multi-target or logic-gated receptors, checkpoint or exhaustion-pathway editing, cytokine-supported and armored constructs, metabolic fitness enhancement, and selected multiplex-editing strategies. In parallel, CAR-NK cells, universal allogeneic CAR-T products, and stem-cell-derived platforms may provide additional options in relapse-prone or heavily pretreated patients, particularly when autologous T-cell fitness, manufacturing feasibility, or repeat dosing is a concern.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>A resistance-guided approach may help align engineered cellular therapy design with the dominant mechanisms of treatment failure in high-risk hematological malignancies. Rather than simply increasing engineering complexity, future CAR-T and CAR-NK development should link each modification to a measurable resistance mechanism, a feasible biomarker, and a clinically testable benefit. Prospective validation, genomic safety assessment, manufacturing consistency, and long-term monitoring will be essential before resistance-matched cellular immunotherapy can be broadly integrated into clinical practice.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fgeed.2026.1878460","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T09:51:56Z","timestamp":1786614716000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Functional genomics\u2013guided design of CAR-T and CAR-NK therapies in hematological malignancies: aligning cellular engineering with immune escape and microenvironmental resistance"],"prefix":"10.3389","volume":"8","author":[{"given":"Shiqi","family":"Cai","sequence":"first","affiliation":[{"name":"Department of Hematology, Sichuan Academy of Medical Sciences and Sichuan People\u2019s Hospital","place":["Chengdu, China"]},{"name":"School of Life Science and Technology, University of Electronic Science and Technology of China","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Hematology, Sichuan Academy of Medical Sciences and Sichuan People\u2019s Hospital","place":["Chengdu, China"]},{"name":"Department of Hematology, The Affiliated Hospital of Southwest Medical University","place":["Luzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Hematology, Sichuan Academy of Medical Sciences and Sichuan People\u2019s Hospital","place":["Chengdu, China"]},{"name":"Department of Hematology, The Affiliated Hospital of Southwest Medical University","place":["Luzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Hematology, Sichuan Academy of Medical Sciences and Sichuan People\u2019s Hospital","place":["Chengdu, China"]},{"name":"School of Life Science and Technology, University of Electronic Science and Technology of China","place":["Chengdu, China"]},{"name":"Department of Hematology, The Affiliated Hospital of Southwest Medical University","place":["Luzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1867","DOI":"10.1016\/j.cell.2016.11.048","article-title":"A multiplexed single-cell CRISPR screening platform enables systematic dissection of the unfolded protein response","volume":"167","author":"Adamson","year":"2016","journal-title":"Cell"},{"key":"B2","volume-title":"Human Gene Therapy Products Incorporating Human Genome Editing; Guidance for Industry","author":"Administration","year":"2024"},{"key":"B3","doi-asserted-by":"publisher","first-page":"S13","DOI":"10.1080\/1547691X.2024.2345158","article-title":"Novel strategies to assess cytokine release mediated by chimeric antigen receptor T cells based on the adverse outcome pathway concept","volume":"21","author":"Alb","year":"2024","journal-title":"J. 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