Inhibition of post-surgery tumour recurrence via a sprayable chemo-immunotherapy gel releasing PD-L1 antibody and platelet-derived small EVs

Background: Melanoma is the most serious type of skin cancer, and surgery is an effective method to treat melanoma. Unfortunately, local residual micro-infiltrated tumour cells and systemic circulating tumour cells (CTCs) are significant causes of treatment failure, leading to tumour recurrence and metastasis. Methods: Small EVs were isolated from platelets by differential centrifugation, and doxorubicin-loaded small EVs (PexD) was prepared by mixing small EVs with doxorubicin (DOX). PexD and an anti-PD-L1 monoclonal antibody (aPD-L1) were co-encapsulated in fibrin gel. The synergistic antitumour efficacy of the gel containing PexD and aPD-L1 was assessed both in vitro and in vivo. Results: Herein, we developed an in situ-formed bioresponsive gel combined with chemoimmunotherapeutic agents as a drug reservoir that could effectively inhibit both local tumour recurrence and tumour metastasis. In comparison with a DOX solution, PexD could better bind to tumour cells, induce more tumour immunogenic cell death (ICD) and promote a stronger antitumour immune response. PexD could enter the blood circulation through damaged blood vessels to track and eliminate CTCs. The concurrent release of aPD-L1 at the tumour site could impair the PD-1/PD-L1 pathway and restore the tumour-killing effect of cytotoxic T cells. This chemoimmunotherapeutic strategy triggered relatively strong T cell immune responses, significantly improving the tumour immune microenvironment. Conclusion: Our findings indicated that the immunotherapeutic fibrin gel could awaken the host innate immune system to inhibit both local tumour recurrence post-surgery and metastatic potential, thus, it could serve as a promising approach to prevent tumour recurrence.

Automated summary

In this study, a bioresponsive gel combined with chemoimmunotherapeutic agents was developed to effectively inhibit both local tumor recurrence and metastasis. The gel promoted tumor immunogenic cell death and induced a strong antitumor immune response. The concurrent release of an anti-PD-L1 antibody impaired the PD-1/PD-L1 pathway and improved the tumor-killing effect of cytotoxic T cells.