Reversing the negative effect of adenosine A1 receptor-targeted immunometabolism modulation on melanoma by a co-delivery nanomedicine for self-activation of anti-PD-L1 DNAzyme

The metabolite adenosine plays critical roles in tumor progression, metastasis and chemoresistance, and the adenosine pathway has been regarded as an important therapeutic target in cancer. Here, we found that adenosine A1 receptor (ADORA1) was overexpressed in melanoma tissue and had a positive association with tumor malignance and advancement from clinical patient samples. The inhibition of ADORA1 could damage melanoma cells with high specificity and induce tumor cells immunogenic cell death (ICD), while PD-L1 was also elevated significantly at cell surface after treatment, indicating a negative effect on tumor immunotherapy. To compensate this drawback, we designed and fabricated a hybrid nanomedicine with DPCPX (an ADORA1 inhibitor) loaded PLGA core and metal-organic framework (MOF) shell via Fe3+/Mn2+-tannic acid (TA) coordination for anti-PD-L1 DNAzyme (Dz) encapsulation. The nanosystem was not only a carrier to co-deliver DPCPX and Dz, but also a metal reservoir to release Mn2+ for self-activation of the metal-dependent Dz for PD-L1 mRNA cleavage. As a result, a co-inhibition of ADORA1 and PD-L1 was realized to strengthen the ICD immune response, thus promoting dendritic cell (DC) maturation, CD8+ T lymphocyte infiltration and activation, and memory T cells production for enhanced immunotherapy. Such combinatorial therapy could effectively control both primary and distal tumor growth with full biocompatibility. This study provides a novel strategy to induce tumor selective ICD, and highlights the benefits of combining ADORA1 inhibitor with PD-L1 blockage via self-active nanomedicine to enhance the melanoma immunotherapy.