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Background Chimeric antigen receptor T (CAR-T) cell therapies are a form of adoptive cell therapy that has shown promising clinical efficacy, especially against hematological cancer, with multiple FDA-approved therapies. Current autologous CART therapy faces significant challenges, such as high cost, long manufacturing timelines, need to tumor-restricted antigens, and variability in product quality due to patient-specific factors. These challenges are pronounced in solid tumors. To overcome these limitations, we are developing an off-the-shelf, gene-edited allogeneic CART cell therapy, which is designed for broad application across solid cancer types by targeting Desmoglein-2 (DSG2).Methods Using our established system, we isolated T cells from healthy donors and engineered them to express a DSG2-directed CAR. To design the allogenic CART, we are employing the multiplex CRISPR-Cas9 gene editing system to knock out TCRαβ (to prevent graft-versus-host disease), β2-microglobulin (B2M) and CIITA (to eliminate MHC class I and II and reduce HVGR). CD54 and CD58 will also be eliminated to protect the designed allogenic CART from NK attack. CAR expression and gene editing efficiency are being confirmed by flow cytometry and sequencing. Functional assays included target cell killing, cytokine release, and proliferation. In vivo efficacy and safety will be evaluated in xenograft mouse models.Results Our preliminary data demonstrate that autologous DSG2 directed CART shows strong anti-tumor activity with favorable safety profile in mouse models. Based on these findings, we are designing universal CART using our previously designed DSG2 CART construct. Current efforts are focused on testing gRNAs for the multiplex CRISPR/Cas9 gene editing system. Gene editing workflows and validation assays are being established as part of this early development phase.Conclusions This work outlines the foundation for developing a universal, gene-edited CAR-T therapy targeting DSG2. Once engineered and validated, this system may serve as a scalable strategy for treating solid tumors.