MRI guided copper deprivator activated immune responses and suppressed angiogenesis for enhanced antitumor immunotherapy.

Abstract

Background: Copper plays an important role in the regulation of PD-L1, suggesting that reducing copper levels within tumors may enhance anti-cancer immunotherapy. Methods: Tumor microenvironment responsive copper nanodeprivator (TMECN) was developed for enhancing immunotherapy of tumor via the cross-link of mercaptopolyglycol bipyridine and dimercaptosuccinic acid modifying FePt nanoalloy using the disulfide bond. Results: Upon entering tumor cells, the disulfide bond in TMECN is cleaved by the overexpressed glutathione, exposing abundance of sulfhydryl groups. Next, TMECN actively captured copper ions in the cancer cells, which triggered the self-assembly of TMECN. The reduced copper not only inhibited tumor neovascularization and PD-L1 transcription but also promoted the ubiquitination and degradation of PD-L1, blocking tumor immune escape. In addition, TMECN catalyzed Fenton reaction and produced reactive oxygen species (ROS) in cancer cells, inducing immunogenic cell death (ICD) of tumor. The inhibition of PD-L1 and the activation of ICD synergistically promoted cytotoxic T lymphocyte infiltration for tumor, evoked robust antitumor immune responses. In addition, the self-assembly of TMECN in tumor induced T₁ to T₂ switchable contrast imaging, which significantly improved accurate diagnosis of tumor. Conclusion: TMECN could effectively inhibit tumor growth and metastases, meanwhile improve MRI contrast enhancement of tumor. The project will offer a simple strategy for enhancing MRI-guided antitumor immunotherapy.