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Piseddu, I.* ; Endres, R.* ; Lanzl, F.* ; Hammann, L.* ; Bérouti, M.* ; Thaler, M.* ; Fahr, L.* ; Fischer, H.* ; Varlamova, V.* ; Gärtig, J.* ; Nixdorf, D.* ; Layritz, P.* ; Marx, C.* ; Hörth, C.* ; Witte, C.* ; Bulut, A.* ; Illig, D.* ; Senz, A.M.* ; Holdt, L.* ; Regel, I.* ; Gottschlich, A.* ; Subklewe, M.* ; Mayerle, J.* ; Anz, D.* ; Kobold, S. ; Linder, A.* ; Hornung, V.*

STING ablation in T cells is required for the efficacy of STING agonists in CAR-T cell immunotherapy of pancreatic cancer.

Gastroenterology 171, 50-65 (2026)

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BACKGROUND & AIMS: Chimeric antigen receptor (CAR) T cells have shown great potential in hematological cancers, but lack efficacy in solid tumors, highlighting the need for novel strategies. STING activation was shown to inflame the tumor microenvironment, but combination of STING agonists and CAR-T cells might be limited by detrimental outcomes of T cell-intrinsic STING activation. In this study, we evaluated the potential of combining STING agonists and CAR-T cells in the context of pancreatic cancer METHODS: We assessed the synergy of CRISPR-Cas9-edited CAR-T cells and the STING agonist diABZI within a T cell exhaustion model in vitro and both xenograft and syngeneic mouse models in vivo. RESULTS: Combination of STING-ablated CAR-T cells and diABZI resulted in enhanced cancer cell killing, increased CAR-T cell proliferation, reduced exhaustion and expansion of an effector-memory phenotype in vitro. Mechanistically, superior CAR-T cell functionality required genetic ablation of STING in CAR-T cells and was dependent on cancer cell-intrinsic STING signaling upon STING-agonistic treatment. Moreover, we identified a synergistic feedback loop comprising the T cell-secreted cytokines IFN-γ and TNF, which prime STING signaling within cancer cells, thereby potentiating the outcomes of cancer cell-intrinsic STING activation in inducing ameliorated CAR-T cell states. Ultimately, we could demonstrate that combination of STING^KO CAR-T cells and diABZI was able to provide enhanced tumor control in both xenograft and syngeneic mouse models. This was accompanied by increased intratumoral CAR-T cell numbers and reprogramming of the tumor microenvironment in vivo. CONCLUSION: Our findings suggest that STING^KO CAR-T cells stand to benefit from STING agonists to improve CAR-T cell therapy for immune-deprived cancers such as pancreatic cancer.

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Publication type Article: Journal article

Document type Scientific Article

Keywords Car-t Cells ; Crispr-cas9 ; Pdac ; Sting

ISSN (print) / ISBN 0016-5085

e-ISSN 1528-0012

Journal Gastroenterology

Quellenangaben Volume: 171, Issue: 1, Pages: 50-65

Publisher Elsevier

Publishing Place 1600 John F Kennedy Boulevard, Ste 1800, Philadelphia, Pa 19103-2899 Usa

Reviewing status Peer reviewed

Institute(s) Unit for Clinical Pharmacology (KKG-EKLiP)

Grants Bavarian Cancer Research Center (BZKF)
International doctoral program "i-Target: immunotargeting of cancer"
Elite Network of Bavaria
Melanoma Research Alliance
Marie Sklodowska-Curie Training Network for Optimizing Adoptive T Cell Therapy of Cancer
Horizon 2020 program of the European Union
Marie Sklodowska-Curie Training Network for Tracking and Controlling Therapeutic Immune Cells in Cancer
DFG
Stiftungen zu Gunsten der Medizinischen Fakultaet
Novartis Foundation
ERC
Deutsche Forschungsgemeinschaft (German Research Foundation)
Foerderprogramm fuer Forschung und Lehre der Medizinischen Fakultaet der LMU
BZKF (Adrian Gottschlich and TANGO to Sebastian Kobold)
Horizon program of the European Union
Else Kroener-Fresenius-Stiftung
German Cancer Aid
Deutsche Jose Carreras Leukaemie Stiftung
Hector Foundation
Bavarian Research Foundation
Bruno and Helene Joester Foundation
Monika Kutzner Foundation
Rurainski Foundation
Brigitte and Dr Konstanze Wegener Foundation
DKTK School of Oncology
Fritz-Bender Foundation
SFB TRR 338
European Research Council
Ernst Jung Stiftung
Institutional Strategy LMUexcellent of LMU Munich (within the framework of the German Excellence Initiative)
Go-Bio-Initiative
M4-Award of the Bavarian Ministry for Economical Affairs
Bundesministerium fuer Bildung und Forschung
German Research Foundation