000152221 001__ 152221
000152221 005__ 20250401114419.0
000152221 0247_ $$2doi$$a10.1038/s41590-025-02103-z
000152221 0248_ $$2sideral$$a143383
000152221 037__ $$aART-2025-143383
000152221 041__ $$aeng
000152221 100__ $$aRea, Anna
000152221 245__ $$aEnhancing human NK cell antitumor function by knocking out SMAD4 to counteract TGFß and activin A suppression
000152221 260__ $$c2025
000152221 5060_ $$aAccess copy available to the general public$$fUnrestricted
000152221 5203_ $$aTransforming growth factor beta (TGFβ) and activin A suppress natural killer (NK) cell function and proliferation, limiting the efficacy of adoptive NK cell therapies. Inspired by the partial resistance to TGFβ of NK cells with SMAD4 haploinsufficiency, we used CRISPR–Cas9 for knockout of SMAD4 in human NK cells. Here we show that SMAD4KO NK cells were resistant to TGFβ and activin A inhibition, retaining their cytotoxicity, cytokine secretion and interleukin-2/interleukin-15-driven proliferation. They showed enhanced tumor penetration and tumor growth control, both as monotherapy and in combination with tumor-targeted therapeutic antibodies. Notably, SMAD4KO NK cells outperformed control NK cells treated with a TGFβ inhibitor, underscoring the benefit of maintaining SMAD4-independent TGFβ signaling. SMAD4KO conferred TGFβ resistance across diverse NK cell platforms, including CD19-CAR NK cells, stem cell-derived NK cells and ADAPT-NK cells. These findings position SMAD4 knockout as a versatile and compelling strategy to enhance NK cell antitumor activity, providing a new avenue for improving NK cell-based cancer immunotherapies.
000152221 536__ $$9info:eu-repo/grantAgreement/ES/DGA/B29-23R$$9info:eu-repo/grantAgreement/ES/MCIU-AEI/PID2020-113963RB-I00 Desasignar
000152221 540__ $$9info:eu-repo/semantics/openAccess$$aby-nc-nd$$uhttp://creativecommons.org/licenses/by-nc-nd/3.0/es/
000152221 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000152221 700__ $$aSantana-Hernández, Sara
000152221 700__ $$aVillanueva, Javier
000152221 700__ $$aSanvicente-García, Marta
000152221 700__ $$aCabo, Mariona
000152221 700__ $$aSuárez-Olmos, Jesús
000152221 700__ $$aQuimis, Fabricio
000152221 700__ $$aQin, Mengjuan
000152221 700__ $$aLlorens, Eduard
000152221 700__ $$aBlasco-Benito, Sandra
000152221 700__ $$aTorralba-Raga, Lamberto
000152221 700__ $$aPérez, Lorena
000152221 700__ $$aBhattarai, Bishan
000152221 700__ $$aAlari-Pahissa, Elisenda
000152221 700__ $$aGeorgoudaki, Anna-Maria
000152221 700__ $$aBalaguer, Francesc
000152221 700__ $$aJuan, Manel
000152221 700__ $$0(orcid)0000-0003-0154-0730$$aPardo, Julián$$uUniversidad de Zaragoza
000152221 700__ $$aCelià-Terrassa, Toni
000152221 700__ $$aRovira, Ana
000152221 700__ $$aMöker, Nina
000152221 700__ $$aZhang, Congcong
000152221 700__ $$aColonna, Marco
000152221 700__ $$aSpanholtz, Jan
000152221 700__ $$aMalmberg, Karl-Johan
000152221 700__ $$aMontagut, Clara
000152221 700__ $$aAlbanell, Joan
000152221 700__ $$aGüell, Marc
000152221 700__ $$aLópez-Botet
000152221 700__ $$aMuntasell, Aura
000152221 7102_ $$11011$$2566$$aUniversidad de Zaragoza$$bDpto. Microb.Ped.Radio.Sal.Pú.$$cÁrea Inmunología
000152221 773__ $$g(2025), [33 pp.]$$pNat. immunol.$$tNATURE IMMUNOLOGY$$x1529-2908
000152221 8564_ $$s4804800$$uhttps://zaguan.unizar.es/record/152221/files/texto_completo.pdf$$yVersión publicada
000152221 8564_ $$s2535828$$uhttps://zaguan.unizar.es/record/152221/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000152221 909CO $$ooai:zaguan.unizar.es:152221$$particulos$$pdriver
000152221 951__ $$a2025-04-01-11:03:04
000152221 980__ $$aARTICLE