Strategies to eliminate native T cell receptors for adoptive T cell therapies

Adoptive T cell therapy has revolutionized modern medicine by harnessing and engineering T cells to selectively target disease-specific antigens. While scientists have developed numerous innovative methods to enhance T cell therapies, strategies to eliminate the native T cell receptor (TCR) have particularly accelerated the field. In TCR T cell therapy, mispairing between native and introduced TCR chains and competition for CD3 binding can compromise therapeutic efficacy and safety. In the context of allogeneic T cell therapies, residual TCR expression can lead to graft-versus-host disease, a life-threatening complication. Effective elimination of native TCRs is therefore essential for improving both safety and efficacy of adoptive T cell therapies. Multiple strategies targeting the TCR at the genomic, transcriptomic, or proteomic level have been developed to achieve effective TCR disruption, each characterized by its own advantages and limitations. This review provides a comprehensive overview of current strategies to eliminate the native TCR in human T cells, highlighting the strengths and weaknesses of each method.