Anti-CTLA-4 antibody self-presented dendritic cell nanovesicles boost the immunotherapy of hepatocellular carcinoma after microwave ablation.

Microwave ablation (MWA) is a frequently adopted regional therapy for treating hepatocellular carcinoma (HCC) in clinic. However, incomplete microwave ablation (IMWA) is often inevitable due to the restraint of ablating large tumors or tumors in special locations, resulting in a high recurrence rate of HCC. Moreover, the most promising immune checkpoint blockade (ICB)-based immunotherapy is raising hindered by the toxicity and insufficient immune response. To overcome these barriers, we conjugate small nanovesicle (smDV)-derived from matured dendritic cells (mDCs) with anti-CTLA-4 antibody (smDV-aCTLA-4) using a metabolic tagging technology, which could trigger the infiltration of cytotoxic T cells (CTLs) and adopted tumor-infiltrating lymphocytes (TILs) in residual HCC after IMWA. In HCC microenvironment, the administration of smDV-aCTLA-4 could promote antigen presentation and immune checkpoint suppression to activate CTLs and improve the safety of anti-CTLA-4 antibody. Moreover, the anti-tumor efficacy of CTLs elicited by smDV-aCTLA-4 could also be further enhanced by anti-programmed death 1 (aPD-1) antibody. In addition, compared to the adoptive TILs therapy, the treatment using smDV-aCTLA-4-bonded TILs (smDV-aCTLA-4@TILs) could promote the proliferation and infiltration of cytotoxic TILs in residual HCC after IMWA. Our results clearly evidenced the potency of a new type of engineered DC nanovesicles in reducing HCC recurrence after IMWA.