Tumor-responsive nanoparticles precisely overcome hypoxia-mediated STING dysfunction to unleash potent antitumor immunity.

The Stimulator of Interferon Genes (STING) pathway plays a central role in anti-tumor immunity by mobilizing both the innate and adaptive immunity. However, hypoxia, a tumor hallmark was shown to severely constrain immune responses and lead to suboptimal therapeutic efficacy. Through bioinformatic analyses, we revealed that hypoxia directly repress STING-pathway-related genes. Furthermore, we developed tumor-targeted pH-responsive nanoparticles (SPF) to overcome hypoxia-induced STING dysfunction for amplifying immune responses. The nanoparticles (NPs) effectively accumulate and reoxygenate the hypoxic tumor, achieving a potent STING activation with enhanced secretion of type-I IFNs and other inflammatory cytokines. Moreover, SPF are capable of decreasing Tregs and polarizing M2 to M1 macrophages, thus creating an immune-promoting microenvironment to unleash cascade immune response. In colon cancer models, SPF NPs strongly inhibited tumor growth with 33% tumor-free over 50 days and long-term immune memory. Importantly, robust STING activation was achieved in human tumor samples with a substantial 782.3-fold of IFN-β and 1683.8-fold CXCL10 over control, highlighting the significance of hypoxia overcoming on STING activation in clinical settings. This study demonstrates a tumor-responsive nanomedicine with precise spatiotemporal control of hypoxia relief to overcome STING resistance, guiding the rational design and clinical translation of therapeutics for next-generation cancer immunotherapy.