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Background Immunotherapy, particularly immune checkpoint blockade (ICB), has shown clinical promise, but its efficacy in colorectal cancer (CRC) remains limited due to a complex immunosuppressive tumor microenvironment (TIME) characterized by dysregulated CD47/SIRPα and PD-1/PD-L1 pathways, T-cell exhaustion, and immunosuppressive cell infiltration. Novel strategies that effectively reshape the TIME are urgently needed.Methods We developed bioinspired nanodevices (SPCM@DMgTi-ADM) consisting of dendritic titanium-magnesium nanodevices (DMgTi) serving as both sonosensitizer and carrier for aldometanib (ADM). These were coated with genetically engineered cell membranes displaying SIRPα/PD-1 decoy receptors (SPCM). The nanodevices were designed to simultaneously block both immune checkpoint axes, deliver Mg 2+ and ADM, and enable sonodynamic therapy (SDT). Antitumor mechanisms were investigated through in vitro assays and in vivo studies in CRC models.Results SPCM@DMgTi-ADM effectively blocked SIRPα/CD47 and PD-1/PD-L1 pathways, initiating TIME remodeling. Released Mg 2+ induced LFA-1 conformational changes on CD8+ T cells, enhancing tumor infiltration and cytotoxicity. Mg2+ also potentiated ADM-induced AMPK activation, which synergized with SDT to trigger autophagy-dependent ferroptosis and robust immunogenic cell death (ICD). Released dsDNA subsequently activated the cGAS-STING pathway, feedback-inhibiting GPX4 to sustain ferroptotic stress, thereby establishing a self-amplifying ferroptosis-dsDNA release-cGAS-STING-GPX4 inhibition circuit that amplified anti-tumor immunity. Both in vitro and in vivo studies confirmed efficient tumor ablation and systemic immune activation (IDDF2026-ABS-0297 Figure 1. Mechanistic diagram of sonodynamic-triggered nanoimmunotherapy integrating AMPK cascade activation, autophagy-dependent ferroptosis, and cGAS-STING signaling).Conclusions This bioinspired nanodevice achieves cascade reinforcement between AMPK activation and cGAS-STING activation through synergistic immune checkpoint blockade, metabolic modulation, and sonodynamic therapy, offering a clinically translatable strategy for precision CRC immunotherapy.Abstract IDDF2026-ABS-0297 Figure 1