Immune-activated microspheres for enhanced chemoembolization of hepatocellular carcinoma by blocking the adenosine A2A receptor.

Transcatheter arterial chemoembolization (TACE) stands as the frontline strategy for unresectable hepatocellular carcinoma (HCC), effectively eliminating cancer cells through direct cytotoxicity and immunogenic cell death (ICD). However, TACE triggers rapid tumor apoptosis, which promotes the release of intracellular ATP into the extracellular space. This ATP is sequentially hydrolyzed to adenosine (ADO) by ectonucleotidases (CD39 and CD73) overexpressed in the tumor microenvironment (TME), resulting in ADO accumulation. The ensuing ADO pathway-mediated immunosuppression via adenosine 2A receptors (A2AR) signaling severely limits TACE-induced ICD efficacy, resulting in poor prognosis. To address this, we developed gelatin microspheres co-loaded with doxorubicin (DOX) and the A2AR antagonist SCH-58,261, in which SCH-58,261 was loaded into solid lipid nanoparticle (SLNP) due to its poor water solubility. The microspheres (SLNP-SCH/DOX@MS) showed an average size of 49 ± 13 μm, with the capable of complete tumor vascular embolization, and sustained release profiles of both DOX and SCH-58,261 over 30 days. In vitro and in vivo studies indicated that SLNP-SCH/DOX@MS not only enhanced tumor cell apoptosis but also amplified ICD-mediated dendritic cell maturation and antigen presentation. Moreover, SCH-58,261 counteracted TACE-triggered ADO accumulation by competitively binding to A2AR on immune cells, thereby reversing dendritic cell dysfunction and CD8⁺T cell exhaustion. This dual-action strategy synergized ICD-driven immunostimulation with ADO pathway blockade, reshaping the TME. Our findings highlight the potential of SLNP-SCH/DOX@MS to address the delicate equilibrium between ICD-induced immunity and ADO-mediated immunosuppression for improved HCC treatment. STATEMENT OF SIGNIFICANCE: This study introduces a approach to improve transcatheter arterial chemoembolization (TACE) for unresectable hepatocellular carcinoma (HCC) by addressing the adenosine (ADO) pathway, a known barrier to effective immunogenic cell death (ICD). We developed gelatin microspheres co-loaded with doxorubicin (DOX) and the A2AR antagonist SCH-58,261, which significantly enhance TACE-induced immunity by promoting ICD and counteracting ADO-mediated immunosuppression. In vitro and in vivo results demonstrate robust dendritic cell maturation and amplified tumor-specific immune responses, indicating improved antitumor efficacy. This work provides a promising strategy to optimize TACE for HCC treatment, offering our readership a therapeutic solution that bridges cancer treatment and immunomodulation.