On‐Demand Peroxynitrite Overproduction Reprograms Systemic Immune Function for Augmented Sono‐Immunotherapy against Tumor

Abstract The undesirable efficacy of immunotherapy in cancer patients is associated with the inactivation of immune responses in tumor immunosuppressive microenvironment (TIME). The pivotal roles of nitric oxide (NO) and peroxynitrite (ONOO − ) in immunoregulation can augment anticancer immunotherapy. Here, ultrasound (US)‐responsive nanoparticles (NPs), denoted as Cu‐PG NPs, are elaborately constructed to achieve incremental NO release for gas therapy and controlled generation of superoxide anion (O 2 •− ) for sonodynamic therapy (SDT), thereby leading to synergistic in situ ONOO − generation and TIME reprogramming. In vitro and in vivo experimental results collectively confirm that US‐activated Cu‐PG NPs effectively regulate immune circulation, which involves multiple steps to ameliorate compromise immunogenicity without systemic toxicity. These steps comprise the initiation of immunogenic cell death in cancer cells, induction of dendritic cells maturation, promotion of cytotoxic T lymphocytes infiltration, and polarization of macrophages toward the pro‐inflammatory M1 phenotype. Importantly, this therapeutic approach reinforces systemic immunity and elicits immune memory to inhibit the proliferation of distant tumors, particularly integration with anti‐PD‐L1 antibodies. This work proposes the synergistic gas therapy and SDT strategy for generating ONOO − , which holds enormous potential in potentiating immunotherapy sensitivity by further facilitating the coordinated remodeling of TIME.