Cytokine fusion proteins for solid tumor therapy: mechanistic insights and clinical advances

Cytokine fusion proteins are engineered biologics that combine functional modules, such as cytokines, antibodies, or albumin-binding domains, into a single molecular entity. These agents have emerged as promising therapeutic platforms for treating solid tumors. However, their clinical translation remains constrained by the need to achieve potent antitumor activity while mitigating dose-limiting systemic toxicities. Here, we dissect the mechanistic foundations of cytokine fusion protein function by examining key cytokine signaling pathways within the tumor microenvironment. We also provide a comprehensive overview of current engineering strategies and clinical developments, focusing on approaches to optimize pharmacokinetics, enhance tumor-targeted delivery, and achieve therapeutic synergy. Collectively, this Review summarizes the evolving landscape of cytokine fusion protein development and discusses emerging opportunities and challenges that may inform future advances in this field.