Suppressing the Hypoxia-Adenosinergic Axis by a Tailored Nanoreactor for Enhanced Photothermal Immunotherapy

Cell metabolite adenosine can induce extensive and persistent immunosuppression by binding to adenosine receptors on immune cells. Seriously, the hypoxia-driven adenosinergic axis aggravates adenosine accumulation via dephosphorizing immune-activating adenosine triphosphate (ATP) released during immunogenic cell death (ICD). Different from direct adenosine clearance or adenosine receptor blockade or directly using ecto-enzyme (CD39/CD73) antagonist, it is hoped to use an innovative small science engineering to regulate the upstream hypoxia/HIF-1α signal of the hypoxia-adenosinergic axis, thereby reducing the immunosuppressive extracellular adenosine and enhancing ICD-triggered antitumor immunity. PM@Mn is constructed by gradually integrating metformin and MnO₂ on polydopamine (PDA) nanoparticles. PM@Mn can effectively suppress hypoxia-adenosinergic axis via combining catalytic oxygen production with reduced endogenous oxygen consumption. Such motif of hypoxia relief suppresses the metabolism of ATP to adenosine via down-regulating the expression of HIF-1α, CD39, and CD73. Meanwhile, PDA in PM@Mn can induce local tumor ablation and trigger the "vaccine effect" of ICD under near-infrared radiation. In a mouse breast cancer model with low immunogenicity, our strategy can effectively reduce adenosine accumulation, PM@Mn group exhibits 4.51-fold cytotoxic T lymphocyte infiltration and tumor inhibition rate of 75.4%. This study provides a new strategy to advance ICD-triggered antitumor immunity through supressing hypoxia-adenosinergic axis.