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Background CAR-T immunotherapies have shown great success against hematological cancers; however, efficacy against solid tumors has been limited, with the immunosuppressive nature of solid tumors thought to be a main impediment. Mechanisms have been explored to enhance CAR-Ts functionality in the context of solid tumors, including CRISPR/Ca9-mediated inactivation of genes restricting anti-tumor function and persistence. We previously reported use of our CRISPRomics® platform to identify Regnase-1 and Suppressor of Cytokine Signaling 1 (SOCS1) as a top dual-edit combination enhancing the anti-tumor activity of TIL. Applying this insight, we developed the engineered TIL (eTIL®) therapy KSQ-004EX, currently in a phase 1 clinical trial ( NCT06598371). Here, we investigate the impact of inactivating Regnase-1 and SOCS1 in a CAR-T setting, termed engineered CAR-T (eCAR-T), in a pre-clinical xenograft solid tumor model.Methods A mesothelin (MSLN)-targeting CAR was used to evaluate the impact of the dual-inactivation of Regnase-1 and SOCS1 in human eCAR-T cells. Using an internally optimized manufacturing process, eCAR-T cells were produced with high CAR expression and robust knockout of Regnase-1 and SOCS1. eCAR-T cells were assessed in vitro for acute and chronic cytotoxicity and proliferative capacity against endogenous MSLN-expressing HCT116 tumor cells. Anti-tumor efficacy was evaluated in vivo using HCT116 tumor-bearing xenograft models.Results MSLN-targeting eCAR-T cells displayed enhanced antigen-dependent proliferation and cytotoxic function resulting in greatly improved tumor control in a chronic stimulation setting. In xenograft models bearing MSLN-expressing HCT116 tumors, eCAR-T cells demonstrated extensive tumor infiltration. This resulted in improved tumor control and extended survival relative to unedited CAR-T cells, which exhibited only transient efficacy followed by tumor escape. These effects were sustained even when eCAR-T cells were administered at a ten-fold lower dose, indicating substantially higher in vivo potency and expansion.Conclusions Dual-inactivation of Regnase-1 and SOCS1 enhances the potency, expansion, and in vivo efficacy of eCAR-T cells in a solid tumor model, enabling durable tumor control even at reduced doses. Our results support the use of Regnase-1 and SOCS1 disruption as a potential strategy to overcome key barriers in solid tumor treatment, extending the durability and potency of CAR-T therapies beyond hematologic cancers.