Wang Mengdie, Prachyathipsakul Theeraphop, Wisniewski Christi A, Xiong Choua, Goel Shivam, Goel Hira Lal, Karner Emmet R, Mukhopadhyay Dimpi, Gupta Prachi, Majee Aniket, Thayumanavan S, Mercurio Arthur M
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA.
Department of Chemistry, University of Massachusetts, Amherst, MA, USA.
Cell Chem Biol. 2024 Dec 19;31(12):2039-2051.e6. doi: 10.1016/j.chembiol.2024.10.014. Epub 2024 Nov 26.
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.
尽管程序性细胞死亡配体1（PD-L1）最为人所知的是其在免疫抑制中的作用，但肿瘤内在功能也逐渐显现。在此，我们报告表达PD-L1的肿瘤细胞对铁死亡诱导剂如咪唑酮厄拉斯汀（IKE）敏感。PD-L1促进铁死亡敏感性，因为它抑制溶质载体家族7成员11（SLC7A11）的表达并降低谷胱甘肽水平。虽然使用抗PD-L1抗体药物偶联物（ADC）可能有效地将铁死亡诱导剂递送至特定肿瘤群体，但大多数铁死亡诱导剂的化学性质使其无法纳入ADC中。为了克服这一挑战，我们合成了一种抗体纳米凝胶偶联物（ANC），其由与包裹有IKE的纳米凝胶偶联的抗PD-L1抗体组成。这种ANC在体外和体内靶向表达PD-L1的细胞并诱导铁死亡，从而导致肿瘤抑制。重要的是，这种方法优于IKE的全身给药，因为它能够将IKE特异性地增强递送至肿瘤细胞，并且其有效所需的药物剂量更低。
