Immunocytokines in Cancer Immunotherapy: Opportunities and Challenges

Shubo Wang¹Lisha Yao¹Jianying Cai^2*Huiquan Gao^3*FUXIN ZHOU^4*

• ¹Department of Gynecology, The Affiliated Weihai Second Municipal Hospital of Qingdao University, Weihai, China
• ²970th hospital of PLA, Weihai, China, Weihai, China
• ³Yantai Yuhuangding Hospital, Yantai, China
• ⁴University of Freiburg Medical Center, Freiburg, Germany

The clinical use of cytokines is restricted by dose-limiting toxicities (DLT), short half-life, and 3 rapid renal clearance, which collectively hinder administration at therapeutically effective doses. 4 Cytokines fused to antibodies (antibody–cytokine fusion proteins, or immunocytokines) have 5 emerged as a promising strategy to overcome these limitations by directing cytokine payloads to 6 the tumor microenvironment, thereby enhancing antitumor immune responses while reducing 7 off-target effects. Various antibody formats, including intact IgGs and IgG fragments, have 8 been engineered to target tumor-associated cell-surface antigens or extracellular matrix (ECM) 9 components, and fused to a wide range of cytokines. Preclinical studies consistently demonstrate 10 enhanced antitumor efficacy and reduced systemic toxicity compared to unconjugated cytokines, 11 with further synergistic effects observed when combined with chemotherapy, radiotherapy, or 12 immune checkpoint inhibitors. Recent advances include anti-PD-1–based immunocytokines that 13 selectively deliver cytokines to intratumoral CD8+ T cells, restoring their function and driving 14 potent antitumor activity. Despite encouraging results, efficacy and safety concerns remain 15 significant challenges for clinical application. Strategies such as cytokine engineering, prodrug 16 approaches, and rational molecular design are being pursued to enhance therapeutic outcomes 17 while minimizing side effects. This review summarizes the conceptual framework, structural 18 design principles, preclinical and clinical progress, current limitations and potential strategies for 19 future development of immunocytokines in cancer immunotherapy.