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However, the efficacy of these CAR\u2010T cells remains limited mainly due to the heterogeneous expression of tumor antigen and their anergy in the tumor microenvironment (TME). Cytokine\u2010inducible SH2\u2010containing protein (CIS, encoded by the gene\n                    <jats:italic>CISH<\/jats:italic>\n                    ) is a potent intracellular checkpoint inducing T\u2010cell anergy. Here, we identified fibroblast activation protein alpha (FAP\u03b1) as a highly attractive target for CAR\u2010T cell therapy against GBM based on its dual expression pattern (on tumor cells and perivascular cells) in GBM. A panel of nanobodies specific for FAP\u03b1 was isolated, and FAP\u03b1\u2010targeting CAR\u2010T cells were developed using the isolated nanobody to verify their specific cytotoxicity to GBM cells. Furthermore, a non\u2010viral circular single\u2010stranded DNA (cssDNA)\u2010based CRISPR\/Cas9\u2010targeted genome\u2010editing (cssDNA\/CRISPR\/Cas9) technology was used to integrate CAR cassettes at the\n                    <jats:italic>CISH<\/jats:italic>\n                    locus to generate\n                    <jats:italic>CISH<\/jats:italic>\n                    \u2010knockout (\n                    <jats:italic>CISH<\/jats:italic>\n                    \u2010KO) CAR\u2010T cells. The resulting\n                    <jats:italic>CISH<\/jats:italic>\n                    \u2010KO\u2010CAR\u2010T cells exhibited robust proliferation and potent anti\u2010GBM activity in vitro and in vivo. Thus, our results provide novel engineered CAR\u2010T cells with enhanced efficacy against GBM.\n                  <\/jats:p>","DOI":"10.1002\/mco2.70702","type":"journal-article","created":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T06:50:28Z","timestamp":1774594228000},"source":"Crossref","is-referenced-by-count":0,"title":["Non\u2010Viral Cytokine\u2010Inducible SH2 Containing Protein Locus\u2010Specific Integrated Fibroblast Activation Protein Alpha\u2010Targeting Chimeric Antigen Receptor T Cells Achieve Potent Antitumor Efficacy in Glioblastoma"],"prefix":"10.1002","volume":"7","author":[{"given":"Xin","family":"Dong","sequence":"first","affiliation":[{"name":"Department of Radiation Oncology Nanfang Hospital Southern Medical University  Guangzhou Guangdong China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yao","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology Nanfang Hospital Southern Medical University  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