In situ forming pH/ROS-responsive niche-like hydrogel for ultrasound-mediated multiple therapy in synergy with potentiating anti-tumor immunity

Tumor immunosuppressive microenvironment (TIME) often causes suppression of anti-tumor immunity and increases susceptibility to tumor recurrence and metastasis. Herein, a novel in situ niche-like hydrogel with pH/ROS dual-responsive behavior was developed for the first time, which was integrated with inorganic sonosensitizer (TiOx@CaO2) and immune checkpoint inhibitor (aPD-L1) to achieve synergistic enhancement of sonodynamic therapy (SDT) and chemodynamic therapy (CDT), as well as the anti-tumor immune checkpoint blockade (ICB) therapy. Specifically, ultrasound (US) triggers the defective TiOx to elicit SDT, and the O2 produced by CaO2 decomposition is beneficial to relieve the hypoxic environment and contributes to reverse the tumor immunosuppression. Moreover, the generation of H2O2 is helpful to boost the ROS-mediated therapeutic effect and the released Ca2+ can induce the mitochondria damage leading to increasing expression of tumor-related antigens, which was further coordinated with aPD-L1 to achieve enhanced anti-tumor therapeutic efficacy. In vivo results demonstrated such in situ gelatinous hydrogel had good retention capability in tumor region which exerted augmented therapeutic efficacy with effective alleviation of the tumor recurrence and metastasis in a 4T1 triple-negative breast cancer (TNBC) tumor model. Briefly, this novel niche-like multifunctional hydrogel with good biosafety presents a promising candidate for the easily metastasized TNBC.