Chimeric antigen receptor (CAR)-based therapies are presented as innovative treatments for multiple malignancies. Despite their clinical success, there is scientific evidence of the limitations of these therapies mainly due to immunogenicity issues, toxicities associated with the infusion of the product, and relapses of the tumor. As a result, novel approaches are appearing aiming to solve and/or mitigate the harmful effects of CAR-T therapies. These include strategies based on the use of ligands as binding moieties or ligand-based CAR-T cells. Several proposals are currently under development, with some undergoing clinical trials to assess their potential benefits. In addition to these, therapies such as chimeric autoantibody receptor (CAAR), B-cell receptor antigen for reverse targeting (BAR), and even chimeric human leukocyte antigen (HLA) antibody receptor (CHAR) have emerged, benefiting from the advantages of antigenic ligands as antibody-binding motifs. This review focuses on the potential role that ligands can play in current and future antitumor treatments and in other types of diseases, such as autoimmune diseases or problems associated with transplantation.

Funding "Thanks to Immunology department (Hospital Clıńic de Barcelona) and Institute of Biotechnology and Biomedicine (IBB-UAB) for their help during the writing of this article. This work has been partially supported by grants from the Instituto de Salud Carlos III, Spanish Ministry of Health (FIS PI18/00775, PICI18/00012 and complementary grant for CONCORD-023), Fondo Europeo de Desarrollo Regional (FEDER) "una manera de hacer Europa", "La Caixa" Foundation (CP042702/LCF/PR/ GN18/50310007), and Secretaria d'Universitats i Recerca del Departament d'Empresa i Coneixement, Generalitat de Catalunya, project 2020PANDE00079."The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.