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While chimeric antigen receptor (CAR)-engineered T cells have demonstrated remarkable clinical efficacy in B-cell lymphomas, nearly half of patients who initially respond to CAR-T therapy eventually develop resistance and disease progression. In this study, we report the presence of residual drug-tolerant persister (DTP) and resistant lymphoma cells remaining within a highly immunogenic tumor microenvironment (TME) induced by the MCL-1 inhibitor (MCL-1i) S63845. MCL-1 inhibition downregulates MYC and activates the STAT1-interferon inflammatory pathway, promoting cytotoxic T-cell infiltration with reduced tumor-associated myeloid cells both in vitro and in vivo. Sublethal dose of the MCL-1i enhances TME immunogenicity and reawakens anti-tumor immune responses in murine models. We show that MCL-1i and CD19-targeted CAR-T cells reciprocally overcome resistance to each single-agent therapy, and combining MCL-1i with CD19 CAR-T cells significantly improves treatment efficacy, resulting in near-complete eradication of MYC-driven lymphoma in vivo. Together, these findings highlight a synergistic, dual-pronged therapeutic strategy targeting both tumor-intrinsic survival pathways and the immunosuppressive TME. This combinatorial one-two-punch approach offers a promising path to eliminate DTP and residual disease, prevent relapse and pave the way for deep clinical remissions in aggressive B-cell lymphomas.<\/jats:p>","DOI":"10.1038\/s41375-026-02884-8","type":"journal-article","created":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T10:18:11Z","timestamp":1770891491000},"page":"638-648","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Synthetic lethality of MCL-1 inhibition and CAR-T therapy in aggressive B-cell lymphoma"],"prefix":"10.1038","volume":"40","author":[{"given":"Jing","family":"Gao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohong","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allen","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Loryn","family":"Blackburn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lenny","family":"Lei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Xiong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5375-7515","authenticated-orcid":false,"given":"Chengfeng","family":"Bi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1295-3258","authenticated-orcid":false,"given":"Jeffrey W.","family":"Craig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9487-8345","authenticated-orcid":false,"given":"Craig A.","family":"Portell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6270-3065","authenticated-orcid":false,"given":"Marco L.","family":"Davila","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5981-9983","authenticated-orcid":false,"given":"Michael E.","family":"Williams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7632-1594","authenticated-orcid":false,"given":"Jianguo","family":"Tao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,12]]},"reference":[{"key":"2884_CR1","doi-asserted-by":"crossref","unstructured":"Bock TJ, Colonne CK, Fiorenza S, Turtle CJ. 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CA Portell: consultant for AbbVie, AstraZeneca, BeiGene\/BeiOne, Genentech, Jansen, Merck, Pfizer and receiving research support from AbbVie, AstraZeneca, Acerta, BeiGene\/BeiOne, Merck, SeaGen\/Pfizer, Loxo\/Lilly, Genentech. ME Williams: consultant\/advisory Board for AstraZeneca, Beigene, Janssen and receiving grant\/research support from Janssen. J Tao is a founder of NewPath Therapeutics. LLC. The remaining authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"All methods were performed in accordance with relevant guidelines and regulations. All animal studies were approved by the Institutional Animal Care and Use Committee of the University of Virginia (protocol number: 4453). Human peripheral blood mononuclear cells were obtained under protocols approved by the Institutional Review Board of the University of Virginia (protocol number: 00000447), and written informed consent was obtained from all participants.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}]}}