A research team led by ZHAO Yuliang and WANG Hao from the National Center for Nanoscience and Technology (NCNST) of the Chinese Academy of Sciences (CAS), collaborating with XU Wanhai from the Harbin Medical University Cancer Hospital has developed a bispecific glycopeptide (bsGP) regulating the spatial interactions of multiple cell types in tumor microenvironment through “In vivo self-assembly” strategy for inhibiting tumor recurrence.
The results have been published in the Journal of Science Advances (DOI: 10.1126/sciadv.abq8225).
In recent work, WANG’s team and collaborators developed the “In vivo self-assembly” strategy” (Adv. Mater. 2015, 27, 6125), revealed the “assembly-induced retention (AIR) effect” (Adv. Mater. 2022, 34, 2109432), and improved the efficiency of drug delivery in vivo (Nat. Commun. 2019, 10, 4861).
In tumor growth, a dynamic and reciprocal relationship develops between cancer cells and components of the tumor microenvironment (TME) that supports cancer cell survival, local invasion and metastatic dissemination. Complex interactions greatly limit the effectiveness of current therapeutic strategies that block the activity of one target cell.
However, among the immune cells recruited to the tumor site, tumor-associated macrophages (TAM) are particularly abundant and are at the center of the invasion microenvironment. Protumoral tumor-associated macrophages (M2-like TAMs) showed a spatial distribution characteristic of accumulating close to tumor cells early during tumor formation.
In this study, the researchers designed a bsGP that simultaneously targets M2-like TAMs and tumor cells. In the TME, bsGP was cleaved into two residues by specific MMP-2 cleavage. The residue containing mannose can re-educate M2-TAM to the anti-tumor M1 type, thereby recruiting T cells to redirect to tumor cells. Another residue for targeting tumor cells can be assembled to form nanostructure that can long-term arrest of CXCR4 signaling of tumor cells, facilitating T cell infiltration through decreases tumor fibrosis.
Bispecific glycopeptides spatially and temporally regulate the behavior of multiple cells in the TME, realizing the spatial redirected distribution of immune cells (TAM and T cells) on the foci of tumor cells.
In orthotopic bladder tumor model, bsGP substantially reduced the postoperative recurrence of bladder cancer in orthotopic tumor-bearing mice, with a recurrence rate of only 22%, while the recurrence rate up to 89 and 78% in doxycycline and Bacillus Calmette-Guerin (BCG) used in clinic, respectively, which provide a promising therapeutic strategy for the inhibition of tumor recurrence with diverse biomedical applications.
“Faced with tumor heterogeneity, this strategy can achieve the regulation of multiple network nodes, significantly inhibit tumor metastasis and recurrence, which has great prospects for clinical transformation.” said WANG, one of the paper’s corresponding authors.
Bispecific glycopeptides spatiotemporally regulate the behavior of multiple cells in the tumor microenvironment, realizing the spatial redirected distribution of immune cells (tumor-associated macrophages and T cells) on the foci of tumor cells.(Image by WANG Hao et al.)
Contact:
Wang Hao
National Center for Nanoscience and Technology
