Dual-Responsive Nanodelivery System Synergizes Elevation in Hypoxia with PD-L1 Blocking to Activate Systemic Immunity and Inhibit Distant Tumors

The hypoxia of the tumor microenvironment is insufficient to fully activate the efficacy of hypoxia-activated prodrugs (HAPs), while severe hypoxia elevates the expression of the hypoxia-inducible factor (HIF-1α), leading to tumor metastasis and immune evasion. This study has constructed a nanomicelle (HACA/GOx@AF/TPZ) that is composed of a coassembly of hyaluronic acid-cinnamaldehyde Schiff base (HACA), glucose oxidase (GOx), tirapazamine (TPZ), and acriflavine (AF). HACA/GOx@AF/TPZ releases the drugs it carries within the tumor microenvironment: the catalytic oxidation of glucose by GOx eliminates oxygen within the tumor, further activating TPZ and generating cytotoxic free radicals to kill the tumor cells. Meanwhile, AF can specifically inhibit HIF-1α through a multistage response, downregulating the expression of VEGF and facilitating the conversion of the tumor microenvironment (TME) to an antitumor TME, inducing dendritic cell maturation and polarization of M2 macrophages to M1. The "hypoxia-activated immune modulation" combination therapy strategy using HACA/GOx@AF/TPZ may provide more possibilities for combined tumor treatment.