Advanced cytokine-based immunotherapies: targeted cis-delivery strategies for enhanced anti-tumor efficacy and reduced toxicity.

First-generation cancer immunotherapies, such as high-dose interleukin-2 (IL-2), have demonstrated clinical efficacy, but are limited by significant systemic toxicities due to their broad expression of cytokine receptors. This has driven the iterative development of targeted cytokine delivery strategies. Early efforts focused on receptor-biased IL-2 variants designed to attenuate or abrogate IL-2 receptor α (IL-2 Rα/CD25) binding. Subsequently, the concept of "cis-targeting" has emerged as a strategy to deliver cytokines to specific immune cell populations, enhancing anti-tumor responses while mitigating systemic toxicity. This review highlights key common γ-chain cytokines (IL-2, IL-7, IL-15, and IL-21) as well as IL-12, providing an overview of their structures, receptors, as well as their distinct T cell functions. Furthermore, we specifically focus on the current landscape of engineered cytokine variants that facilitate targeted cytokine delivery in cis to specific T cells. By successfully restricting cytokine activity to specific T cell populations, cis-targeting approaches represent a promising strategy in the field, enabling efficient immunotherapies with improved tolerability and enhanced anti-tumor responses.