Multichannel Immune Nanoregulators Suppress Lactic Acid Metabolism and Lactic Acid‐Shaped Acidic Microenvironment to Uproot Anti‐Tumor Immunosuppression

Lactic acid (LA) itself and the LA-shaped acidic tumor microenvironment (TME) are identified as root causes of cancer immunosuppression, and no effective strategies address them. Here a multichannel immune nanoregulator is engineered to dampen acidic TME and repolarize non-inflammatory macrophages to uproot this source of cancer immunosuppression, wherein fluorocarbon chains (FC)-modified mesoporous silica (FM) serves as nanoreactors and carriers to in situ synthesize CaO₂ and load R848, respectively, followed by liposome coating, anti-CD105 modification and FC-mediated O₂ binding in sequence. Both liposome shell and intraparticle FC ensure safe CaO₂ delivery. Ultrasound-triggered FC-binding O₂ burst and liposomes-destruction-enhanced CaO₂ reactions with H⁺ and H₂O produce O₂. This process depletes pre-existing H⁺ and inhibits glycolysis LA production to cut off acidic TME source, and uproots their actions in reshaping cancer immunosuppression, e.g., removing the polarization impetus toward non-inflammatory M2 ones, addressing both symptoms and root causes of cytotoxic T lymphocytes and PD1+ T cells inactivation, etc. The cancer immunosuppression uprooting encourages the anti-tumor efficacy of cancer calcification and intratumoral H₂O₂ accumulation in the immune nanoregulators especially after anti-CD105-mediated active targeting accumulation. Collectively, this work presents a solution to uproot LA and non-inflammatory macrophages-induced cancer immunosuppression.