Zhang Chi, Xu Mengke, Zeng Ziling, Wei Xin, He Shasha, Huang Jingsheng, Pu Kanyi
School of Chemistry, Chemical Engineering and Biotechnology, Nanyang Technological University, 70 Nanyang Drive, Singapore, 637457, Singapore.
Lee Kong Chian School of Medicine, Nanyang Technological University, 59 Nanyang Drive, Singapore, 636921, Singapore.
Angew Chem Int Ed Engl. 2023 Mar 13;62(12):e202217339. doi: 10.1002/anie.202217339. Epub 2023 Feb 10.
Cancer immunotherapy has shown tremendous potential to train the intrinsic immune system against malignancy in the clinic. However, the extracellular matrix (ECM) in tumor microenvironment is a formidable barrier that not only restricts the penetration of therapeutic drugs but also prevents the infiltration of antitumor immune cells. We herein report a semiconducting polymer-based ECM nanoremodeler (SPNcb) to combine photodynamic antitumor activity with cancer-specific inhibition of collagen-crosslinking enzymes (lysyl oxidase (LOX) family) for activatable cancer photo-immunotherapy. SPNcb is self-assembled from an amphiphilic semiconducting polymer conjugated with a LOX inhibitor (β-aminopropionitrile, BAPN) via a cancer biomarker (cathepsin B, CatB)-cleavable segment. BAPN can be exclusively activated to inhibit LOX activity in the presence of the tumor-overexpressed CatB, thus blocking collagen crosslinking and decreasing ECM stiffness. Such an ECM nanoremodeler synergizes immunogenic phototherapy and checkpoint blockade immunotherapy to improve the tumor infiltration of cytotoxic T cells, inhibiting tumor growth and metastasis.
癌症免疫疗法在临床上已显示出训练内在免疫系统对抗恶性肿瘤的巨大潜力。然而，肿瘤微环境中的细胞外基质（ECM）是一个巨大的障碍，它不仅限制治疗药物的渗透，还阻止抗肿瘤免疫细胞的浸润。我们在此报告一种基于半导体聚合物的ECM纳米重塑剂（SPNcb），它将光动力抗肿瘤活性与对胶原蛋白交联酶（赖氨酰氧化酶（LOX）家族）的癌症特异性抑制相结合，用于可激活的癌症光免疫疗法。SPNcb由一种两亲性半导体聚合物通过癌症生物标志物（组织蛋白酶B，CatB）可裂解片段与一种LOX抑制剂（β-氨基丙腈，BAPN）共轭自组装而成。在肿瘤过表达的CatB存在下，BAPN可被特异性激活以抑制LOX活性，从而阻断胶原蛋白交联并降低ECM硬度。这种ECM纳米重塑剂使免疫原性光疗和检查点阻断免疫疗法协同作用，以改善细胞毒性T细胞的肿瘤浸润，抑制肿瘤生长和转移。
