Bioresponsive and immunotherapeutic nanomaterials to remodel tumor microenvironment for enhanced immune checkpoint...

Immune checkpoint blockade (ICB) therapy is a revolutionary approach to treat cancers, but still have limited clinical applications. Accumulating evidence pinpoints the immunosuppressive characteristics of the tumor microenvironment (TME) as one major obstacle. The TME, characterized by acidity, hypoxia and elevated ROS levels, exerts its detrimental effects on infiltrating anti-tumor immune cells. Here, we developed a TME-responsive and immunotherapeutic catalase-loaded calcium carbonate nanoparticles (termed as CAT@CaCO₃ NPs) as the simple yet versatile multi-modulator for TME remodeling. CaCO₃ NPs can consume protons in the acidic TME to normalize the TME pH. CAT catalyzed the decomposition of ROS and thus generated O₂. The released Ca²⁺ led to Ca²⁺ overload in the tumor cells which then triggered the release of damage-associated molecular patterns (DAMP) signals to initiate anti-tumor immune responses, including tumor antigen presentation by dendritic cells. Meanwhile, CAT@CaCO₃ NPs-induced immunosupportive TME also promoted the polarization of the M2 tumor-associated macrophages to the M1 phenotype, further enhancing tumor antigen presentation. Consequently, T cell-mediated anti-tumor responses were activated, the efficacy of which was further boosted by aPD-1 immune checkpoint blockade. Our study demonstrated that local treatment of CAT@CaCO₃ NPs and aPD-1 combination can effectively evoke local and systemic anti-tumor immune responses, inhibiting the growth of treated tumors and distant diseases.