Next-generation interleukin-enhanced immunotherapies: From molecular engineering to armored T-cell architectures

Interleukins-based immunotherapy has been adopted clinically and is actively investigated for the treatment of tumors. Current FDA-approved interleukin therapies are significantly limited by the short half-lives and systemic toxicities. Recent advances include interleukin fusion proteins with enhanced target specificity and effector function. Additionally, integration of synthetic interleukin signaling into chimeric antigen receptor (CAR)-T or T cell receptor (TCR)-T cells augments their activation and sustains effector persistence within the immunosuppressive tumor microenvironment (TME). Together, these strategies aim to potentiate anti-tumor immunity, enhance the specificity while minimizing systemic toxicity. Here, we review recent developments in interleukin-enhanced cancer immunotherapy and discuss existing challenges and potential research opportunities.