Eun Young Jeon¹, Da-som Choi², Seunghyun Choi^3,4, Ju-young Won², Yunju Jo^3,4, Hye-bin Kim², Youngmee Jung^1,5,6, Sang Chul Shin⁷, Hophil Min⁸,  Hae Woong Choi⁴,  Myeong Sup Lee⁹, Yoon Park³, Justin J. Chung^10,11, Hyung-seung Jin²

¹Center for Biomaterials, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, South Korea
²Department of Convergence Medicine, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
³Theragnosis Center, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, South Korea
⁴Department of Life Sciences, Korea University, Seoul, South Korea
⁵School of Electrical and Electronic Engineering, Yonsei University, Seoul, South Korea
⁶Yonsei-KIST Convergence Research Institute, Seoul, South Korea
⁷Technology Support Center, Korea Institute of Science and Technology (KIST), Seoul, South Korea
⁸Doping Control Center, Korea Institute of Science and Technology (KIST), Seoul, South Korea
⁹Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul, South Korea
¹⁰Transdisciplinary Department of Medicine and Advanced Technology, Seoul National University Hospital, Seoul, South Korea
¹¹Department of Medicine, Seoul National University College of Medicine, Seoul, South Korea

Eun Young Jeon and Da-som Choi contributed equally to this study.
CORRESPONDING AUTHORS : Yoon Park, Justin J. Chung, Hyung-Seung Jin

Adoptive cell therapy (ACT) with antigen-specific T cells is a promising treatment approach for solid cancers. Interleukin-2 (IL-2) has been utilized in boosting the efficacy of ACT. However, the clinical applications of IL-2 in combination with ACT is greatly limited by short exposure and high toxicities. Herein, a complex coacervate was designed to intratumorally deliver IL-2 in a sustained manner and protect against proteolysis. The complex coacervate consisted of fucoidan, a specific IL-2 binding glycosaminoglycan, and poly-l-lysine, a cationic counterpart (FPC²). IL-2-laden FPC² exhibited a preferential bioactivity in ex vivo expansion of CD8⁺T cells over Treg cells. Additionally, FPC² was embedded in pH modulating injectable gel (FPC²-IG) to endure the acidic tumor microenvironment. A single intratumoral administration of FPC²-IG-IL-2 increased expansion of tumor-infiltrating cytotoxic lymphocytes and reduced frequencies of myeloid populations. Notably, the activation and persistency of tumor-reactive T cells were observed only in the tumor site, not in the spleen, confirming a localized effect of FPC²-IG-IL-2. The immune-favorable tumor microenvironment induced by FPC²-IG-IL-2 enabled adoptively transferred TCR-engineered T cells to effectively eradicate tumors. FPC²-IG delivery system is a promising strategy for T-cell-based immunotherapies.