This study presents a novel approach for in situ chemodynamic-enhanced sono-immunotherapy using TiSe₂ nanoplates. The research focuses on the in situ redox reaction of TiSe₂ in the tumor microenvironment (TME), which generates chemodynamic agents and enhances immunotherapy. The TiSe₂ nanoplates, when exposed to acidic TME, undergo redox transformation to form TiOₓSe₂ nanoplates containing Ti³⁺/Ti⁴⁺ redox couples, Se (0), and selenate. These redox couples facilitate in situ chemodynamic therapy (CDT) through a Ti³⁺-mediated Fenton-like reaction and consume overexpressed glutathione (GSH) via a Ti⁴⁺-mediated GSH depletion. Additionally, Se ions produced during the redox process promote the maturation of dendritic cells, activating adaptive immune responses. The study also constructs a Z-scheme heterojunction between carbon dots (CDs) and TiSe₂, enhancing the reactive oxygen species (ROS) generation efficiency of TiSe₂. This improvement enhances the sonodynamic activity and amplifies the chemodynamic performance. The combination of in situ CDT and sonodynamic therapy efficiently triggers immunogenic cell death (ICD) through a synergistic therapy, which activates the immune system and enhances antitumor immunity. The in situ CDT-enhanced sono-immunotherapy using CD/TiSe₂ heterojunctions, combined with immune checkpoint blockade, effectively suppresses both primary and distant tumors. The study demonstrates that the CD/TiSe₂ heterojunctions have enhanced sonodynamic properties, with a higher rate constant of ROS generation compared to pristine TiSe₂. The heterojunctions also exhibit improved chemodynamic activity, particularly in acidic TME, due to the in situ redox reaction of Ti⁴⁺ and Se²⁻ ions. The CD/TiSe₂ heterojunctions show significant GSH depletion ability, which is attributed to the presence of Ti⁴⁺. The in vitro and in vivo experiments confirm the therapeutic efficacy of the CD/TiSe₂ heterojunctions, with significant tumor growth inhibition and prolonged survival of mice. The combination of in situ CDT and SDT with immune checkpoint blockade (αPD-L1) further enhances the therapeutic effect, leading to complete eradication of both primary and distant tumors. The study highlights the potential of TiSe₂-based heterojunctions for in situ CDT-enhanced sono-immunotherapy, offering a promising strategy for cancer treatment.This study presents a novel approach for in situ chemodynamic-enhanced sono-immunotherapy using TiSe₂ nanoplates. The research focuses on the in situ redox reaction of TiSe₂ in the tumor microenvironment (TME), which generates chemodynamic agents and enhances immunotherapy. The TiSe₂ nanoplates, when exposed to acidic TME, undergo redox transformation to form TiOₓSe₂ nanoplates containing Ti³⁺/Ti⁴⁺ redox couples, Se (0), and selenate. These redox couples facilitate in situ chemodynamic therapy (CDT) through a Ti³⁺-mediated Fenton-like reaction and consume overexpressed glutathione (GSH) via a Ti⁴⁺-mediated GSH depletion. Additionally, Se ions produced during the redox process promote the maturation of dendritic cells, activating adaptive immune responses. The study also constructs a Z-scheme heterojunction between carbon dots (CDs) and TiSe₂, enhancing the reactive oxygen species (ROS) generation efficiency of TiSe₂. This improvement enhances the sonodynamic activity and amplifies the chemodynamic performance. The combination of in situ CDT and sonodynamic therapy efficiently triggers immunogenic cell death (ICD) through a synergistic therapy, which activates the immune system and enhances antitumor immunity. The in situ CDT-enhanced sono-immunotherapy using CD/TiSe₂ heterojunctions, combined with immune checkpoint blockade, effectively suppresses both primary and distant tumors. The study demonstrates that the CD/TiSe₂ heterojunctions have enhanced sonodynamic properties, with a higher rate constant of ROS generation compared to pristine TiSe₂. The heterojunctions also exhibit improved chemodynamic activity, particularly in acidic TME, due to the in situ redox reaction of Ti⁴⁺ and Se²⁻ ions. The CD/TiSe₂ heterojunctions show significant GSH depletion ability, which is attributed to the presence of Ti⁴⁺. The in vitro and in vivo experiments confirm the therapeutic efficacy of the CD/TiSe₂ heterojunctions, with significant tumor growth inhibition and prolonged survival of mice. The combination of in situ CDT and SDT with immune checkpoint blockade (αPD-L1) further enhances the therapeutic effect, leading to complete eradication of both primary and distant tumors. The study highlights the potential of TiSe₂-based heterojunctions for in situ CDT-enhanced sono-immunotherapy, offering a promising strategy for cancer treatment.