Lysosome‐Targeted Self‐Adjuvanting Ammonia Nanogenerator Potentiates Hepatocellular Carcinoma Immunotherapy via Ammonia Death

ABSTRACT Ammonia death is a recently identified form of regulated cell death with unique molecular mechanisms and prominent anticancer activity. Nevertheless, its efficacy is severely restricted by the absence of tumor‐targeted ammonia delivery vehicles and poorly defined immunogenic properties. Herein, we develop a lysosome‐targeted ammonia nanogenerator (denoted AlN@HA) to induce ammonia death in hepatocellular carcinoma (HCC) cells and boost HCC immunotherapy. Following CD44 receptor‐mediated endocytosis, AlN@HA preferentially accumulates within lysosomes and undergoes in situ hydrolysis to produce excessive ammonia and nanoscopic aluminum hydroxide (Al(OH) 3 ). Intralysosomal ammonia overload further drives lysosomal alkalinization and membrane permeabilization, autophagic flux blockade, and mitochondrial dysfunction. This sequential signaling cascade elicits tumor cell ammonia death and triggers robust immunogenic cell death. Meanwhile, the hydrolytic byproduct Al(OH) 3 functions as an intrinsic adjuvant to facilitate dendritic cell maturation. Additionally, ammonia‐mediated neutralization of intratumor lactic acid reverses the immunosuppressive tumor microenvironment. In vivo results verify that AlN@HA‐initiated ammonia death markedly suppresses local tumor proliferation and activates systemic antitumor immune responses, thereby sensitizing HCC to antiprogrammed cell death 1 immunotherapy. This study clarifies the immunological features of tumor ammonia death, establishes a lysosome‐targeted ammonia delivery strategy, and highlights ammonia death as a viable synergistic modality for HCC combination immunotherapy.