Synergistic Cancer Immunotherapy by Inducing Immunogenic Cell Death and Blocking the CD39-Adenosine Pathway Using a...

Background: The immunosuppressive tumor microenvironment (TME), driven by the CD39-mediated conversion of immunostimulatory ATP to immunosuppressive adenosine (ADO), limits cancer immunotherapy. Research design and methods: Here, we developed a nanoparticle (NP) for combined chemo-immunotherapy by co-delivering the ICD inducer doxorubicin (DOX) and a CD39 inhibitor (ARL67156). The amphiphilic polymer PEG2k-b-P(DMAEMA-co-DPAEMA)-b-PTDMAEMA self-assembled into NPs with stable drug loading and rapid, pH-triggered drug release in the acidic TME. Results: In vitro, NPs@DOX induced immunogenic cell death (ICD) and ATP release, while NPs/ARL effectively inhibited CD39. The co-loaded NPs (NPs@DOX/ARL) synergistically enhanced extracellular ATP accumulation by combining increased release with decreased degradation, leading to superior dendritic cell maturation. In vivo, NPs@DOX/ARL demonstrated enhanced tumor accumulation, significant tumor growth inhibition, and robust activation of anti-tumor T-cell immunity. Conclusions: This work presents a promising nanoplatform that targets the ATP-ADO axis to amplify ICD and reverse immunosuppression for enhanced cancer immunotherapy.