文献类型：期刊文献

英文题名：Improving combination cancer immunotherapy by manipulating dual immunomodulatory signals with enzyme-triggered, cell-penetrating peptide-mediated biomodulators

作者：Pang, Guibin[1]; Chen, Piao[1]; Cao, Xuewei[1,3]; Yu, Huan[5]; Zhang, Leshuai W.[5]; Zhao, Jian[1,3]; Wang, Fu-Jun[2,3,4]

机构：[1] State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237, China; [2] New Drug R&D Center, Zhejiang Fonow Medicine Co., Ltd., 209 West Hulian Road, Zhejiang, Dongyang, 322100, China; [3] ECUST-FONOW Joint Research Center for Innovative Medicines, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237, China; [4] Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, China; [5] School for Radiological and Interdisciplinary Sciences [RAD-X], State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, 215123, China

年份：2023

卷号：12

期号：3

起止页码：776

外文期刊名：Biomaterials Science

收录：EI(收录号：20240215340316)

语种：英文

外文关键词：Antigen-antibody reactions - Cell proliferation - Chemical activation - Diseases - Macrophages - Peptides - Scaffolds (biology) - Tumors

摘要：Immunosuppressive tumor microenvironments challenge the effectiveness of protein-based biopharmaceuticals in cancer immunotherapy. Reestablishing tumor cell immunogenicity by enhancing calreticulin (CRT) exposure is expected to improve tumor immunotherapy. Given that CRT translocation is inherently modulated by phosphorylated eIF2α, the selective inhibition of protein phosphatase 1 (PP1) emerges as an effective strategy to augment tumor immunogenicity. To harness the PP1-disrupting potential of GADD34-derived motifs and address their limited intracellular delivery, we integrated these sequences into an enzyme-triggered, cell-penetrating peptide-mediated chimeric protein scaffold. This design not only facilitates efficient cytoplasmic delivery of these immunostimulatory motifs to induce "eat-me" signaling, but also provides a versatile platform for combination immunotherapy. Fabrication of biomodulators with cytotoxic BLF1 provides additional "eat-me" signaling through phosphatidylserine exposure or that with an immunomodulatory designed ankyrin repeat protein disables "don't-find-me" signaling by antagonizing PD-L1. Notably, these bifunctional biomodulators exhibit remarkable ability to induce macrophage phagocytosis, dendritic cell maturation, and CD8+ T activation, ultimately substantially inhibiting tumor growth. This study presents a modular genetic coding strategy for PP1-centered therapies that enables seamless integration of immunostimulatory sequences into protein-based anti-tumor cocktail therapies, thereby offering novel alternatives for improving antitumor efficacy. ? 2024 The Royal Society of Chemistry.