Background/Objectives: CTLA4 (Cytotoxic T-Lymphocyte Antigen 4) is a key immune checkpoint that plays a principal part in controlling T-cell activation and maintaining immune homeostasis. CTLA4 haploinsufficiency (CTLA4^+/−) results in severe autoimmune disorders and increased susceptibility to infections, often associated with dysregulated T cell activity. CTLA4^+/− patients experience life-threatening complications and exhibit moderate survival rates that can vary significantly, depending on the treatment of associated autoimmune phenotypes. Current therapeutic approaches primarily use immunosuppressives and monoclonal antibodies to modulate the immune response; however, their effectiveness and specificity are often limited. In this study, we aimed to develop a novel therapy approach for CTLA4 haploinsufficiency utilizing the CRISPR activation system (CRISPRa) to enhance wild-type CTLA4 allele expression. Methods: The CRISPR/Cas9 system has become a widely used method for precise genome editing, allowing for targeted gene regulation. We applied a CRISPRa-based strategy to induce endogenous CTLA4 expression using appropriate cellular models and evaluated transcriptomic changes. Results: CRISPRa-mediated activation enabled increased CTLA4 expression, suggesting the feasibility of restoring physiological expression levels. Conclusions: This approach may provide a basis for developing CRISPRa-based strategies to restore immune regulation and improve clinical outcomes in CTLA4^+/− patients.