Immunocytokines in cancer: a safety perspective

Immunocytokines (ICs) are engineered biologics comprising a fusion of cytokines to antibodies, designed to deliver targeted cytokines to diseased tissues and mitigate the severe safety challenges associated with systemic cytokine therapy. A rapidly growing number of clinical trials have evaluated ICs, largely based on IL-2, IL-12, and TNF-α, across multiple cancer indications. Although these therapeutics often show improved safety profiles compared to systemic cytokine therapy, clinically relevant toxicities can still occur, including vascular leak syndrome (VLS), hypotension, cytokine release syndrome (CRS), cytopenias, hepatic injury, and local antigen-directed inflammatory toxicities. Although many of these adverse events are manageable, further attenuation is essential to achieve optimal efficacious dosing and to enable combination regimens. Mechanistically, IC toxicities arise through the contribution of both the antibody-mediated target binding and the cytokine moiety. These dual contributors therefore necessitate modality-specific safety considerations. In this focused narrative review, we discuss safety risks associated with clinically advanced IL-2, IL-12 and TNF-α-based ICs, outline potential underlying mechanisms and highlight cytokine- and format-specific factors. We further discuss selected non-clinical mitigation strategies, immunogenicity and translational safety considerations, and outline future directions for developing safer next-generation ICs.