A bispecific glycopeptide spatiotemporally regulates tumor microenvironment for inhibiting bladder cancer recurrence

Authors：An, Hong -Wei; Hou, Da -Yong; Yang, Jia; Wang, Zi-Qi; Wang, Man -Di; Zheng, Rui; Zhang, Ni-Yuan; Hu, Xing-Jie; Wang, Zhi-Jia; Wang, Lu; Liu, Di; Hao, Jun-Feng; Xu, Wanhai^*; Zhao, Yuliang^*; Wang, Hao^*

Source：Science Advances, 2023, 9(9): eabq8225.

DOI：10.1126/sciadv.abq8225

• THERAPY

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.

• Institution
  哈尔滨医科大学; 中国科学院; 中国科学院研究生院; 国家纳米科学中心