Achieving Immune Activation by Suppressing the IDO1 Checkpoint with Sono-Targeted Biobromination for Antitumor Combination Immunotherapy

Indoleamine-2,3-dioxygenase-1 (IDO1) pathogenically suppresses immune cell infiltration and promotes tumor cell immune escape by overmetabolizing tryptophan to <i>N</i>-formyl kynurenine in the tumor microenvironment (TME). However, it remains challenging for IDO1 immune checkpoint inhibitors to achieve a significant potency of progression-free survival. Here, we developed a breakthrough in IDO1 inhibition by sono-targeted biobromination reaction using immunostimulating hypobromic-<i>P</i>-phenylperoxydibenzoic acid-linked metallic organic framework nanomedicine (H-MOF NM) to remodel the TME from debrominated hypoxia into hypobromated normoxia and activate the IDO1 immune pathway with <i>in vitro</i> and <i>in vivo</i> remarkable antitumor efficacy. H-MOF NM contains Br⁺ and O^- active ingredients with an enlarged band gap to deactivate IDO1 through an innovative biochemical mechanism, taking control over brominating IDO1 amino acid residues at the active sites in the remodeled TME and subsequently activating the immune response, including DC maturation, T-cell activation, and macrophage polarization. Importantly, the H-MOF NM achieves multiple immune responses with high tumor regression potency by combination sono-immunotherapy. This study describes an excellent IDO1 inhibition strategy through the development of immune biobrominative H-MOF nanomedicine and highlights efficient combination immunotherapy for tumor treatment.