Reprogramming Adenosine-Driven Tumor Immunosuppression With a Carrier-Free Nanoplatform for Self-Amplifying Antitumor...

Tumor microenvironment (TME) is a metabolically dynamic niche where dysregulated purinergic signaling plays a pivotal role in shaping antitumor immunity. Although immunogenic cell death (ICD) induces the release of extracellular ATP (eATP) to initiate immune activation, the overexpression of ectonucleotidases rapidly degrades eATP into immunosuppressive adenosine, thereby attenuating therapeutic efficacy. To overcome this challenge, we here report a biomimetic nanoplatform (CADF@TA) engineered via coordination-driven self-assembly that reprograms the TME into a sustained bioenergetic reservoir by promoting eATP accumulation while inhibiting its degradation into adenosine. This carrier-free nanoplatform is constructed by co-assembling ectonucleotidase inhibitor ARL-67156 (ARL) and oligonucleotide (CpG) with Fe²⁺ and doxorubicin (DOX). Within this architecture, DOX functions as an inducer of intracellular ATP release through ICD ("pump"), whereas ARL acts as a molecular lock that concurrently inhibits CD39 and CD73 to prevent ATP degradation ("lock"). This "pump-and-lock" mechanism maintains an eATP-enriched microenvironment to promote immune cell recruitment, while CpG serves as a robust adjuvant to facilitate dendritic cell maturation and subsequent CD4⁺ and CD8⁺ T cell activation. The elicited immune response further amplifies tumor apoptosis and replenishes the eATP pool, establishing a self-amplifying immunostimulatory feedback loop. Collectively, this work presents a carrier-free nanoplatform that overcomes the adenosine-mediated immunosuppression through metabolic reprogramming, enabling a self-amplifying immunostimulatory cascade for enhanced antitumor therapy.