The present disclosure provides interferon receptor agonists with improved safety profiles and therapeutic indices. The interferon receptor agonists are attenuated through masking and/or reduced receptor binding as compared to a wild-type interferon. IFN receptor agonists optionally further comprise a targeting moiety, e.g., a targeting moiety that recognizes a tumor- or immune cell-associated antigen and directs the interferon receptor agonist to a tumor site and/or tumor-reactive immune cells. The disclosure further provides pharmaceutical compositions comprising the interferon receptor agonists, and methods of use of the interferon receptor agonists in therapy, as well as nucleic acids encoding the interferon receptor agonists, recombinant cells that express the interferon receptor agonists and methods of producing the interferon receptor agonists.