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

Abstract 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 CaO 2 and load R848, respectively, followed by liposome coating, anti‐CD105 modification and FC‐mediated O 2 binding in sequence. Both liposome shell and intraparticle FC ensure safe CaO 2 delivery. Ultrasound‐triggered FC‐binding O 2 burst and liposomes‐destruction‐enhanced CaO 2 reactions with H + and H 2 O produce O 2 . 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 H 2 O 2 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.