MMP-responsive transformation nanomaterials with TAP antagonist to boost immune checkpoint therapy

The clinical effect of immune checkpoint therapy is limited by the poor blocking efficiency of immune checkpoints and the insufficient infiltration of tumor-specific T cells. Here, we constructed enzyme-responsive PVA-peptide conjugates (PPCs) to achieve re-assembly with enhanced accumulation in the tumor region, enable enhanced PD-L1 occupancy and improve the blocking efficiency. The self-assembled PPC-1 nanoparticles can enter tumor environment, whereas the enzyme-cleavable peptide was digested under overgenerated matrix metalloproteinases (MMP). The accumulated PPC-1 simultaneously transformed into beta-sheet fibrous structures around the solid tumor and remained stable for over 96 h, which led to efficiently interrupting the PD-1/PD-L1 interaction. Upon introduction of the IAP antagonists, the non-classical NF-kappa B pathway of dendritic cells was activated and increased the infiltration of T cells in tumors. With the synergistic contribution of IAP antagonists from the substantial increase in expression of chemokines (CCL5 and CXCL9) and adequate T-cell infiltration in tumor sites, PPC-1 improved the biodistribution and accumulation of PD-L1 antagonists in tumor regions ultimately realizing higher-performance (P < 0.01) tumor growth inhibition efficiency (similar to 80%) than PPC-2 group (similar to 58%) in B 16E10 tumor-bearing mice. The growth of the second tumor at the distal end was obviously inhibited (P < 0.01) after the resection of the primary tumor. The combined efficacy was similar to that observed in a Pan02 pancreatic cancer tumor model. This strategy aims to offer novel perspective for the development of locational assembly platforms in vivo and the optimal design of immune checkpoint combination therapy.

Automated summary

The study developed enzyme-responsive PVA-peptide conjugates (PPCs) to improve the blocking efficiency of immune checkpoints in tumor-specific T cells. The self-assembled PPC-1 nanoparticles were able to enter tumor environment and effectively interrupt the PD-1/PD-L1 interaction. By introducing IAP antagonists, the study also increased the infiltration of T cells in tumors, improving the biodistribution and accumulation of PD-L1 antagonists and achieving higher tumor growth inhibition efficiency.