Highly Active Strontium Peroxide Nanoparticles Induce Alkalization/Oxidation to Potentiate Cancer Immuno-Metabolic Therapy

Hepatocellular carcinoma (HCC), one of the most deadly threats to human health, is characterized by its tumor microenvironment (TME) with poor immunogenicity and hyperactive lactate metabolism-induced acidosis. To relieve the immune suppression and boost anticancer immune responses in HCC, we have developed an oxidation–alkalization-based immuno-metabolic regulation strategy, to induce immunogenic cell death (ICD) and reprogram cellular immunity via metabolic regulation. To this end, highly active strontium peroxide nanoparticles (SrPN) are synthesized by a mild liquid-phase approach to effectively initiate rapid alkalization and strengthen oxidative stress upon hydrolysis, and finally induce ICD in HCC cells to facilitate damage-associated molecular pattern release, dendritic cell maturation, and macrophage polarization toward M1 type via H 2 O 2 -mediated oxidative stress and alkalization-driven acidosis reversal. Interestingly, it has been found that lactic acid significantly amplifies the glycolytic level in macrophages and metabolically promotes SrPN-induced macrophage M1 polarization, which evokes anticancer immunity through the intratumoral metabolite leveraging. Eventually, SrPN exhibits especially high tumor inhibition efficiency in an orthotopic HCC model via clinically friendly ultrasound-guided percutaneous injection by the combined cancer cell killing and immuno-metabolic regulation of TME. This work presents an alkalization-strengthened oxidative stress-based immune-metabolic regulation strategy to potentiate the HCC immune-microenvironment for biocompatible and effective destruction.