Provided herein are immunomodulatory polypeptides containing first and second subunits of a cytokine or a chemokine connected by a joining region containing a targeting moiety that binds to a target molecule. In some aspects, the disclosure further relates to engineered cells and compositions comprising the immunomodulatory polypeptides and methods for their administration to subjects. In some embodiments, the cells engineered to contain the immunomodulatory polypeptide, such as T cells, further contain a genetically engineered antigen receptor that specifically binds to antigens, such as a chimeric antigen receptor (CAR). In some embodiments, features of the polypeptides, engineered cells, and methods provide for improved treatment of diseases or disorders, such as by reducing adverse effects of cytokine or chemokine therapy, or increasing activity, efficacy and/or persistence or decreasing immunogenicity of adoptive cell therapy.
