The ammonia-senescence ratchet drives an adaptation-senescence-ammonioptosis transition in liver cancer

Abstract

Senescence suppresses tumor proliferation while exposing survival dependencies, motivating separate, sequential steps of senescence induction and senescent-cell clearance. Whether senescence-sustaining metabolism can instead be overdriven to trigger cell-autonomous death remains unknown. Senescent cells generate ammonia through glutaminolysis to buffer intracellular acidification, yet extracellular ammonia can impair anti-tumor immunity, leaving unexplored whether ammonia can instead drive tumor-cell-intrinsic death. Here, we reverse this logic and identify a self-reinforcing ammonia-senescence ratchet in which ammonia accumulation promotes senescence, whereas senescence reciprocally enhances ammoniagenesis, progressively driving tumor cells from metabolic adaptation through senescence to ammonioptosis. Reducing intracellular ammonia suppressed senescence and cell death, whereas ammonia repletion restored lethality. We engineered acid-responsive H3B-120@CoGd-LDH (HBCG) to preferentially amplify tumor-cell ammonia by reinforcing senescence and ammoniagenesis, restricting ammonia disposal and weakening lysosomal buffering. HBCG limited extracellular ammonia accumulation and CD8+ T-cell exposure in co-cultures, induced ammonioptosis in patient-derived liver-cancer organoids and suppressed tumor growth in immunocompetent mice. This work reveals that adaptation, senescence and ammonioptosis can be connected through escalating intracellular ammonia stress, providing a mechanistic framework for understanding stress-driven tumor-cell fate transitions.