CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology (NCNST), Beijing 100190, China.
Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing 100049, China.
Sci Adv. 2023 Mar;9(9):eabq8225. doi: 10.1126/sciadv.abq8225. Epub 2023 Mar 1.
Up to 75% of bladder cancer patients suffer from recurrence due to postoperative tumor implantation. However, clinically used Bacillus Calmette-Guerin (BCG) treatment failed to inhibit the recurrence. Here, we report a bispecific glycopeptide (bsGP) that simultaneously targets CD206 on tumor-associated macrophages (TAMs) and CXCR4 on tumor cells. bsGP repolarizes protumoral M2-like TAMs to antitumor M1-like that mediated cytotoxicity and T cell recruitment. Meanwhile, bsGP is cleaved by the MMP-2 enzyme to form nanostructure for the long-term inhibition of CXCR4 downstream signaling, resulting in reduced tumor metastasis and promoted T cell infiltration. In orthotopic bladder tumor models, bsGP reduced the postoperative recurrence rate to 22%. In parallel, the recurrence rates of 89 and 78% were treated by doxycycline and BCG used in clinic, respectively. Mechanistic studies reveal that bsGP reduces the matrix microenvironment barrier, increasing the spatially redirected CD8 T cells to tumor cells. We envision that bis-targeting CD206 and CXCR4 may pave the way to inhibit tumor metastasis and recurrence.
多达 75%的膀胱癌患者在手术后因肿瘤植入而复发。然而，临床上使用的卡介苗（BCG）治疗未能抑制复发。在这里，我们报告了一种双特异性糖肽（bsGP），它可以同时靶向肿瘤相关巨噬细胞（TAMs）上的 CD206 和肿瘤细胞上的 CXCR4。bsGP 将促肿瘤的 M2 样 TAMs 重新极化为抗肿瘤的 M1 样，介导细胞毒性和 T 细胞募集。同时，bsGP 被 MMP-2 酶切割形成纳米结构，长期抑制 CXCR4 下游信号转导，从而减少肿瘤转移并促进 T 细胞浸润。在原位膀胱癌模型中，bsGP 将术后复发率降低到 22%。同时，临床上使用的强力霉素和 BCG 的复发率分别为 89%和 78%。机制研究表明，bsGP 降低了基质微环境屏障，增加了空间重定向的 CD8 T 细胞对肿瘤细胞的浸润。我们设想，双靶向 CD206 和 CXCR4 可能为抑制肿瘤转移和复发开辟道路。
