黄芩素通过自噬降解作用锚定CD274/PD-L1以增强抗肿瘤免疫力。
Baicalein tethers CD274/PD-L1 for autophagic degradation to boost antitumor immunity.
作者信息
Hao Bingjie, Lin Shumeng, Liu Haipeng, Xu Junfang, Chen Li, Zheng Tiansheng, Zhang Wen, Dang Yifang, Reiter Russel J, Li Chaoqun, Zhai Hong, Xia Qing, Fan Lihong
机构信息
Institute of Energy Metabolism and Health, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
Department of Respiratory Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
出版信息
Autophagy. 2025 May;21(5):917-933. doi: 10.1080/15548627.2024.2439657. Epub 2024 Dec 22.
Immune checkpoint inhibitors, especially those targeting CD274/PD-L1yield powerful clinical therapeutic efficacy. Thoughmuch progress has been made in the development of antibody-basedCD274 drugs, chemical compounds applied for CD274degradation remain largely unavailable. Herein,baicalein, a monomer of traditional Chinese medicine, isscreened and validated to target CD274 and induces itsmacroautophagic/autophagic degradation. Moreover, we demonstrate thatCD274 directly interacts with MAP1LC3B (microtubule associatedprotein 1 light chain 3 beta). Intriguingly, baicalein potentiatesCD274-LC3 interaction to facilitate autophagic-lysosomal degradationof CD274. Importantly, targeted CD274. degradation via baicaleininhibits tumor development by boosting T-cell-mediated antitumorimmunity. Thus, we elucidate a critical role of autophagy-lysosomalpathway in mediating CD274 degradation, and conceptually demonstratethat the design of a molecular "glue" that tethers the CD274-LC3interaction is an appealing strategy to develop CD274 inhibitors incancer therapy.: ATTECs: autophagy-tethering compounds; AUTACs: AUtophagy-TArgeting Chimeras; AUTOTACs: AUTOphagy-TArgeting Chimeras; AMPK: adenosine 5'-monophosphate (AMP)-activated protein kinase; BiFC: bimolecular fluorescence complementation; BafA1: bafilomycin A; CD274/PD-L1/B7-H1: CD274 molecule; CQ: chloroquine; CGAS: cyclic GMP-AMP synthase; DAPI: 4'6-diamino-2-phenylindole; FITC: fluorescein isothiocyanate isomer; GFP: green fluorescent protein; GZMB: granzyme B; IHC: immunohistochemistry; ICB: immune checkpoint blockade; KO: knockout; KD: equilibrium dissociation constant; LYTAC: LYsosome-TArgeting Chimera; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MST: microscale thermophoresis; NFAT: nuclear factor of activated T cells; NFKB/NF-kB: nuclear factor kappa B; NSCLC: non-small-cell lung cancer; PDCD1: programmed cell death 1; PROTACs: PROteolysis TArgeting Chimeras; PRF1: perforin 1; PE: phosphatidylethanolamine; PHA: phytohemagglutinin; PMA: phorbol 12-myristate 13-acetate; STAT: signal transducer and activator of transcription; SPR: surface plasmon resonance; TILs: tumor-infiltrating lymphocyte; TME: tumor microenvironment.
免疫检查点抑制剂，尤其是靶向CD274/PD-L1的抑制剂，具有强大的临床治疗效果。尽管基于抗体的CD274药物研发已取得很大进展，但用于CD274降解的化合物仍极为匮乏。在此，我们筛选并验证了中药单体黄芩素可靶向CD274并诱导其巨自噬/自噬性降解。此外，我们证明CD274直接与微管相关蛋白1轻链3β（MAP1LC3B）相互作用。有趣的是，黄芩素增强了CD274与LC3的相互作用，以促进CD274的自噬-溶酶体降解。重要的是，通过黄芩素靶向降解CD274可通过增强T细胞介导的抗肿瘤免疫来抑制肿瘤发展。因此，我们阐明了自噬-溶酶体途径在介导CD274降解中的关键作用，并从概念上证明设计一种连接CD274-LC3相互作用的分子“胶水”是开发癌症治疗中CD274抑制剂的一种有吸引力的策略。：ATTECs：自噬连接化合物；AUTACs：自噬靶向嵌合体；AUTOTACs：自噬靶向嵌合体；AMPK：5'-单磷酸腺苷（AMP）激活的蛋白激酶；BiFC：双分子荧光互补；BafA1：巴弗洛霉素A；CD274/PD-L1/B7-H1：CD274分子；CQ：氯喹；CGAS：环鸟苷酸-腺苷酸合成酶；DAPI：4',6-二脒基-2-苯基吲哚；FITC：异硫氰酸荧光素异构体；GFP：绿色荧光蛋白；GZMB：颗粒酶B；IHC：免疫组织化学；ICB：免疫检查点阻断；KO：敲除；KD：平衡解离常数；LYTAC：溶酶体靶向嵌合体；LIR：LC3相互作用区域；MAP1LC3/LC3：微管相关蛋白1轻链3；MST：微量热泳；NFAT：活化T细胞核因子；NFKB/NF-κB：核因子κB；NSCLC：非小细胞肺癌；PDCD1：程序性细胞死亡1；PROTACs：蛋白酶靶向嵌合体；PRF1：穿孔素1；PE：磷脂酰乙醇胺；PHA：植物血凝素；PMA：佛波醇12-肉豆蔻酸酯13-乙酸酯；STAT：信号转导子和转录激活子；SPR：表面等离子体共振；TILs：肿瘤浸润淋巴细胞；TME：肿瘤微环境。
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