Triggered\nCascade-Activation Nanoplatform to Alleviate\nHypoxia for Effective Tumor Immunotherapy Guided by NIR-II Imaging

Hypoxia\nis one of the most typical features among various types\nof solid tumors, which creates an immunosuppressive tumor microenvironment\n(TME) and limits the efficacy of cancer treatment. Alleviating hypoxia\nbecomes a key strategy to reshape hypoxic TME which improves cancer\nimmunotherapy. However, it remains challenging to perform tumor precision\ntherapy with controllable switches through hypoxia-activated gene\nediting and prodrugs to alleviate hypoxia. In this study, silica-coated\nsecond near-infrared window (NIR-II) emitting silver sulfide quantum\ndots are used as the carrier to load the Clustered Regularly Interspaced\nShort Palindromic Repeats/Cas9 (CRISPR/Cas9) system to target hypoxia-inducible\nfactor-1 (HIF-1α) and guide tumor-targeted imaging. To reduce\nthe off-target effects in nontumor cells and better control safety\nrisks, a TME-triggered cascade-activation nanodiagnostic and therapeutic\nplatform (AA@Cas-H@HTS) is designed, which achieves the hypoxia activation\nof prodrug tirapazamine (TPZ) and spatiotemporal release of CRISPR/Cas9\nribonucleoprotein. Tumor hypoxia is greatly alleviated by the synergistic\nfunction of HIF-1α depletion by gene editing and TPZ activation.\nImportantly, targeting HIF-1α disrupts the programmed cell death\n1/programmed cell death ligand 1 (PD-1/PD-L1) signaling pathway, which\neffectively reshapes the immune-suppressive TME and activates T cell-mediated\nantitumor immunity. Taken together, we have provided a TME-triggered\ncascade-activation nanoplatform to alleviate hypoxia for improved\ncancer immunotherapy.