Advances in IL-2 Family Cytokine-Based Cancer Therapies: Overcoming Challenges Through Molecular Engineering and Delivery Strategies

Cytokines of the common γ-chain family (IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21) are pivotal in regulating immune responses and hold significant promise for cancer immunotherapy. However, their clinical efficacy has been hindered by short serum half-life, pleiotropic off-target effects, and dose-limiting systemic toxicities such as cytokine release syndrome. This review provides a comprehensive overview of recent advancements designed to overcome these limitations. Molecular engineering strategies, including PEGylation, Fc-fusion, muteins, and next-generation approaches like pro-cytokines and split-cytokines, which aim to enhance stability and receptor specificity. To minimize systemic toxicity and achieve high, tumor-localized cytokine concentrations, a variety of innovative delivery systems have been developed, ranging from polymer- and lipid-based nanoparticles to biological vehicles such as oncolytic viruses and cell-based therapies. Furthermore, these delivery systems are designed to respond to both intrinsic and extrinsic stimuli, enabling spatial and temporal control over cytokine activity. By synthesizing current progress and remaining challenges, this review outlines the future trajectory of cytokine-based therapeutics in achieving precise and safe anti-tumor immunity.