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000274320 1001_ $$00000-0002-8054-5603$$aVornholz, Larsen$$b0
000274320 245__ $$aSynthetic enforcement of STING signaling in cancer cells appropriates the immune microenvironment for checkpoint inhibitor therapy.
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000274320 520__ $$aImmune checkpoint inhibitors (ICIs) enhance anticancer immunity by releasing repressive signals into tumor microenvironments (TMEs). To be effective, ICIs require preexisting immunologically 'hot' niches for tumor antigen presentation and lymphocyte recruitment. How the mutational landscape of cancer cells shapes these immunological niches remains poorly defined. We found in human and murine colorectal cancer (CRC) models that the superior antitumor immune response of mismatch repair (MMR)-deficient CRC required tumor cell-intrinsic activation of cGAS-STING signaling triggered by genomic instability. Subsequently, we synthetically enforced STING signaling in CRC cells with intact MMR signaling using constitutively active STING variants. Even in MMR-proficient CRC, genetically encoded gain-of-function STING was sufficient to induce cancer cell-intrinsic interferon signaling, local activation of antigen-presenting cells, recruitment of effector lymphocytes, and sensitization of previously 'cold' TMEs to ICI therapy in vivo. Thus, our results introduce a rational strategy for modulating cancer cell-intrinsic programs via engineered STING enforcement to sensitize resistant tumors to ICI responsiveness.
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000274320 7001_ $$00000-0002-0495-2944$$aIsay, Sophie E$$b1
000274320 7001_ $$00000-0002-3958-4205$$aKurgyis, Zsuzsanna$$b2
000274320 7001_ $$aStrobl, Daniel C$$b3
000274320 7001_ $$00000-0002-6844-1334$$aLoll, Patricia$$b4
000274320 7001_ $$aMosa, Mohammed H$$b5
000274320 7001_ $$00000-0001-7464-7921$$aLuecken, Malte D$$b6
000274320 7001_ $$aSterr, Michael$$b7
000274320 7001_ $$aLickert, Heiko$$b8
000274320 7001_ $$00000-0002-0253-9056$$aWinter, Christof$$b9
000274320 7001_ $$00000-0002-3928-6080$$aGreten, Florian R$$b10
000274320 7001_ $$0P:(DE-He78)7b2b456070135aa203453dc9991aa33d$$aFarin, Henner$$b11$$udkfz
000274320 7001_ $$00000-0002-2419-1943$$aTheis, Fabian J$$b12
000274320 7001_ $$00000-0002-8381-3597$$aRuland, Jürgen$$b13
000274320 773__ $$0PERI:(DE-600)2810933-8$$a10.1126/sciadv.add8564$$gVol. 9, no. 11$$n11$$peadd8564$$tScience advances$$v9$$x2375-2548$$y2023
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