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Rational design of immune gene therapy combinations via in vivo CRISPR activation screening of tumor microenvironment modulators

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE255517 | GEO | 2026/01/23

REPOSITORIES: GEO

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Rational design of immune gene therapy combinations via in vivo CRISPR activation screening of tumor microenvironment modulators [CRISPR]

Project description:The hostile tumor microenvironment (TME) is major challenge for cancer immunotherapies. Here, we design and perform TME-targeted in vivo CRISPR activation (CRISPRa) screens to uncover factors that promote anti-tumor immunity, culminating in rationally designed immune gene therapy combinations. Through adeno-associated virus (AAV) delivery, we find that multiplexed activation of pooled immunoregulatory genes encoding antigen presentation, cytokine, and co-stimulation molecules (APCM) leads to enhanced anti-tumor immunity. A CRISPRa screen targeting APCM genes in metastatic tumors identifies CD80, TNFSF14, CXCL10, TNFSF18, TNFSF9, and IFNG as the top immunostimulatory candidates. Further optimization pinpoints 4-1BBL(TNFSF9) + IFNG + IL12B (4II) as a potent streamlined therapeutic combination. AAV delivered 4II has potent in vivo anti-tumor efficacy in multiple tumor models, by enhancing tumor antigen presentation while simultaneously promoting the infiltration, activation, and expansion of anti-tumor T cells. We further demonstrate that APCM therapy synergizes with CAR-T therapy against human solid tumors in vivo. CRISPRa screens and gene activation systems targeting APCM factors thus represent a powerful approach for rapid development of off-the-shelf immune gene therapies against solid tumors.

2026-01-26 | GSE255515 | GEO

Rational design of immune gene therapy combinations via in vivo CRISPR activation screening of tumor microenvironment modulators [APCM_Screen_CLCG4I]

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Rational design of immune gene therapy combinations via in vivo CRISPR activation screening of tumor microenvironment modulators [APCM_scRNASeq_mouseCD45]

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Rational design of immune gene therapy combinations via in vivo CRISPR activation screening of tumor microenvironment modulators [APCM_BulkRNASeq_OT1]

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Rational design of immune gene therapy combinations via in vivo CRISPR activation screening of tumor microenvironment modulators [scRNA-seq]

2026-01-26 | GSE255516 | GEO

Rational design of immune gene therapy combinations via in vivo CRISPR activation screening of tumor microenvironment modulators [Bulk RNA-seq]

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Rational design of immune gene therapy combinations via in vivo CRISPR activation screening of tumor microenvironment modulators [CRISPR]

Project description:Rational design of immune gene therapy combinations via in vivo CRISPR activation screening of tumor microenvironment modulators [CRISPR]

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Rational design of immune gene therapy combinations via in vivo CRISPR activation screening of tumor microenvironment modulators

Project description:Rational design of immune gene therapy combinations via in vivo CRISPR activation screening of tumor microenvironment modulators

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Rational design of immune gene therapy combinations via in vivo CRISPR activation screening of tumor microenvironment modulators [APCM_Screen_CLCG4I]

Project description:Rational design of immune gene therapy combinations via in vivo CRISPR activation screening of tumor microenvironment modulators [APCM_Screen_CLCG4I]

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Rational design of immune gene therapy combinations via in vivo CRISPR activation screening of tumor microenvironment modulators [APCM_scRNASeq_mouseCD45]

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