Mengdie Wang, Theeraphop Prachyathipsakul, Christi A. Wisniewski, Choua Xiong, Shivam Goel, Hira Lal Goel, Emmet R. Karner, Dimpi Mukhopadhyay, Prachi Gupta, Aniket Majee, S. Thayumanavan, Arthur M. Mercurio
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Therapeutic induction of ferroptosis in tumors using PD-L1 targeting antibody nanogel conjugates
Although programmed cell death ligand 1 (PD-L1) is best known for its role in immune suppression, tumor-intrinsic functions are emerging. Here, we report that tumor cells that express PD-L1 are sensitive to ferroptosis inducers such as imidazole ketone erastin (IKE). PD-L1 promotes ferroptosis sensitivity because it suppresses SLC7A11 expression and diminishes glutathione levels. Although the use of anti-PD-L1 antibody drug conjugates (ADCs) could be effective for the delivery of ferroptosis inducers to specific tumor populations, the chemistry of most ferroptosis inducers precludes their incorporation in ADCs. To overcome this challenge, we synthesized an antibody nanogel conjugate (ANC) comprised of an anti-PD-L1 antibody conjugated to a nanogel encapsulated with IKE. This ANC targets PD-L1-expressing cells in vitro and in vivo and induces ferroptosis, resulting in tumor suppression. Importantly, this approach is superior to systemic administration of IKE because it enables enhanced delivery of IKE specifically to tumor cells and it requires lower drug doses for efficacy.
Cell Chemical BiologyBiochemistry, Genetics and Molecular Biology-Molecular Medicine
CiteScore
14.70
自引率
2.30%
发文量
143
期刊介绍:
Cell Chemical Biology, a Cell Press journal established in 1994 as Chemistry & Biology, focuses on publishing crucial advances in chemical biology research with broad appeal to our diverse community, spanning basic scientists to clinicians. Pioneering investigations at the chemistry-biology interface, the journal fosters collaboration between these disciplines. We encourage submissions providing significant conceptual advancements of broad interest across chemical, biological, clinical, and related fields. Particularly sought are articles utilizing chemical tools to perturb, visualize, and measure biological systems, offering unique insights into molecular mechanisms, disease biology, and therapeutics.