Universal CAR-T Cell Therapy for Cancer Treatment: Advances and Challenges.

This review aims to explore the development, challenges, and future directions of UCAR cell therapy as a scalable alternative to autologous CAR-T for cancer treatment. Consequently, limitations of autologous CAR-T, including long production, variable quality, and cost, drive off-the-shelf UCAR development to standardize manufacturing and improve access. Current UCAR-T cell strategies focus on mitigating the risks of graft-vs.-host disease and host-vs.-graft rejection through advanced gene editing technologies, including clustered regularly interspaced short palindromic repeat-associated system Cas9-mediated knockout of the T cell receptor, human leukocyte antigen, and cluster of differentiation 52 (CD52). Beyond conventional T cells, cell types such as double-negative T cells, γδT cells, and virus-specific T cells are being engineered with CARs to improve tumor targeting and minimize off-tumor toxicity. UCAR-T therapy is frequently used for hematologic malignancies, including acute lymphoblastic leukemia, non-Hodgkin lymphoma, and multiple myeloma, with efficacy and safety supported by numerous clinical studies. Although trials for solid tumors (e.g., CYAD-101, CTX130) show modest responses, challenges such as tumor heterogeneity and T cell exhaustion remain. Future research should focus on optimizing gene editing precision, integrating combination therapies, and advancing scalable manufacturing platforms. With expanded targets and cell types, UCAR therapies show promise for both hematologic and solid tumors, reshaping cancer treatment and patient outcomes.