A bispecific glycopeptide spatiotemporally regulates tumor microenvironment for inhibiting bladder cancer recurrence
Menée in vitro et à l'aide de xénogreffes de tumeur de la vessie sur des modèles murins, cette étude met en évidence l'intérêt d'un glycopeptide bispécifique, ciblant simultanément la protéine CD206 des macrophages associés à la tumeur et le récepteur CXCR4 des cellules cancéreuses, pour inhiber le développement de métastases et réduire le risque de récidive post-opératoire
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.
Science Advances 2023