Enzymatically Switchable Pyroptosis‐Inducing Polymer Conjugate to Coordinate Host Immune Responses in Cancer Immunotherapy
Abstract
Abstract Gasdermin‐D‐mediated pyroptosis, an immunogenic cell death predominantly occurring in antigen‐presenting cells, is pivotal in orchestrating innate and adaptive immunity. Therefore, this dynamic process holds significant potential as an effective cancer immunotherapy strategy. However, its adequate spatiotemporal control in cancer remains challenging. An Enzymatically switchable Pyroptosis‐Inducing polymer Conjugate (EPIC) is reported that selectively triggers chemiluminescence resonance energy transfer (CRET) in the lysosome in the presence of Cathepsin B, abundant in cancer cells. When exposed to cancer cells in vitro, EPIC generates reactive oxygen species via self‐immolation‐mediated CRET, triggering lysosomal membrane disintegration, followed by activation of the signaling cascade that cleaves gasdermin‐D. Cleaved gasdermin‐D forms pyroptotic pores in the cancer cell membrane, promoting the efflux of damage‐associated molecular patterns and inflammatory cytokines. When systemically administered into the tumor‐bearing mice, EPIC provokes a robust immune response by promoting dendritic cell maturation and reinvigorating cytotoxic NK cells. Combination of EPIC with anti‐PD‐1 antibody enhanced infiltration of tumor‐specific cytotoxic T cells and promoted memory T cells, resulting in a durable remission of established tumors with complete tumor regression in more than half of the treated mice. Overall, EPIC has potential as a nanoplatform with multifaceted advantages for precise and effective cancer immunotherapy.
Article Details
Authors (17)
Torsha Ghosh
School of Chemical Engineering College of Engineering Sungkyunkwan University Suwon 16419 Republic of Korea
Jueun Jeon
Center for Systems Biology
Van Hieu Duong
School of Chemical Engineering College of Engineering Sungkyunkwan University Suwon 16419 Republic of Korea
Farrokhroo Ghahari
School of Chemical Engineering College of Engineering Sungkyunkwan University Suwon 16419 Republic of Korea
Seok Ho Song
School of Chemical Engineering College of Engineering Sungkyunkwan University Suwon 16419 Republic of Korea
Jeongyun Kim
Department of Health Sciences and Technology SAIHST Sungkyunkwan University Seoul 06351 Republic of Korea
Minsung Park
Department of Health Sciences and Technology SAIHST Sungkyunkwan University Seoul 06351 Republic of Korea
Chaemin Lee
School of Chemical Engineering College of Engineering Sungkyunkwan University Suwon 16419 Republic of Korea
Duc Anh Lai
Department of Chemistry, Southern Methodist University , Dallas, Texas 75275,
Heegun Kang
School of Chemical Engineering College of Engineering Sungkyunkwan University Suwon 16419 Republic of Korea
Sohyun Cho
Department of MetaBioHealth SKKU Institute for Convergence Sungkyunkwan University Suwon 16419 Republic of Korea
Dong Gil You
Department of Chemical Engineering and Biotechnology Tech University of Korea Siheung 15073 Republic of Korea
Jeongjin Lee
School of Chemical Engineering College of Engineering Sungkyunkwan University Suwon 16419 Republic of Korea
Sol Shin
School of Chemical Engineering College of Engineering Sungkyunkwan University Suwon 16419 Republic of Korea
Hak Soo Choi
Chan‐Hwa Chung
School of Chemical Engineering College of Engineering Sungkyunkwan University Suwon 16419 Republic of Korea
Jae Hyung Park
School of Chemical Engineering College of Engineering Sungkyunkwan University Suwon 16419 Republic of Korea