TY  - JOUR
AU  - Vornholz, Larsen
AU  - Isay, Sophie E
AU  - Kurgyis, Zsuzsanna
AU  - Strobl, Daniel C
AU  - Loll, Patricia
AU  - Mosa, Mohammed H
AU  - Luecken, Malte D
AU  - Sterr, Michael
AU  - Lickert, Heiko
AU  - Winter, Christof
AU  - Greten, Florian R
AU  - Farin, Henner
AU  - Theis, Fabian J
AU  - Ruland, Jürgen
TI  - Synthetic enforcement of STING signaling in cancer cells appropriates the immune microenvironment for checkpoint inhibitor therapy.
JO  - Science advances
VL  - 9
IS  - 11
SN  - 2375-2548
CY  - Washington, DC [u.a.]
PB  - Assoc.
M1  - DKFZ-2023-00534
SP  - eadd8564
PY  - 2023
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:36921054
DO  - DOI:10.1126/sciadv.add8564
UR  - https://inrepo02.dkfz.de/record/274320
ER  -