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Vornholz, L.* ; Isay, S.E.* ; Kurgyis, Z.* ; Strobl, D.C. ; Loll, P.* ; Mosa, M.H.* ; Luecken, M. ; Sterr, M. ; Lickert, H. ; Winter, C.* ; Greten, F.R.* ; Farin, H.F.* ; Theis, F.J. ; Ruland, J.*

Synthetic enforcement of STING signaling in cancer cells appropriates the immune microenvironment for checkpoint inhibitor therapy.

Sci. Adv. 9:eadd8564 (2023)

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Immune checkpoint inhibitors (ICIs) enhance anticancer immunity by releasing repressive signals into tumor microenvironments (TMEs). To be effective, ICIs require preexisting immunologically "hot" niches for tumor antigen presentation and lymphocyte recruitment. How the mutational landscape of cancer cells shapes these immunological niches remains poorly defined. We found in human and murine colorectal cancer (CRC) models that the superior antitumor immune response of mismatch repair (MMR)-deficient CRC required tumor cell-intrinsic activation of cGAS-STING signaling triggered by genomic instability. Subsequently, we synthetically enforced STING signaling in CRC cells with intact MMR signaling using constitutively active STING variants. Even in MMR-proficient CRC, genetically encoded gain-of-function STING was sufficient to induce cancer cell-intrinsic interferon signaling, local activation of antigen-presenting cells, recruitment of effector lymphocytes, and sensitization of previously "cold" TMEs to ICI therapy in vivo. Thus, our results introduce a rational strategy for modulating cancer cell-intrinsic programs via engineered STING enforcement to sensitize resistant tumors to ICI responsiveness.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Mismatch Repair Deficiency; Colorectal-cancer; Tumors; Expression; Activation; Responses; Blockade; Cxcl10; Sensor; Web

ISSN (print) / ISBN 2375-2548

e-ISSN 2375-2548

Journal Science Advances

Quellenangaben Volume: 9, Issue: 11, Article Number: eadd8564

Publisher American Association for the Advancement of Science (AAAS)

Publishing Place Washington, DC [u.a.]

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Computational Biology (ICB)
Institute of Diabetes and Regeneration Research (IDR)
Lung Health and Immunity (LHI)
Institute of Stem Cell Research (ISF)

Grants Leukemia & Lymphoma Society
European Research Council (ERC) under the European Union
Elite Network of Bavaria
Hessen State Ministry for Higher Education, Research and the Arts
Deutsche Forschungsgemeinschaft (DFG, German Research foundation)
Deutsche Forschungsgemeinschaft
German Federal Ministry of Health
Ministry of Higher Education, Research
Arts of the State of Hessen (HMWK)