A Hybrid ManganeseNanoparticle Simultaneously EliminatesCancer Stem Cells and Activates STING Pathway to Potentiate CancerImmunotherapy

Current immunotherapies such as immune checkpoint blockades (ICBs) have revolutionized oncotherapy regime; however, their responsiveness and efficiencies among patients with head and neck squamous cell carcinoma (HNSCC) remain quite limited. The existence of therapeutic-refractory cancer stem cells (CSCs) and inadequate activation of the cyclic guanosine monophosphate-adenosine monophosphate synthase/interferon gene stimulator (cGAS/STING) signaling pathway greatly contribute to immune evasion and immunotherapeutic resistance. Herein, we sought to develop a nanocomplex for HNSCC therapy by simultaneous CSCs eradication and STING activation. PTC209/MnO₂@BSA (bovine serum albumin) nanoparticles (PMB NPs) synthesized <i>via</i> a facile and green process are reported, wherein the released manganese (Mn) ions under acidic tumor microenvironment significantly enhance cGAS-STING signals and facilitate the dendritic cells maturation to unleash the T-cell-mediated immune response. Meanwhile, PTC209 released from PMB NPs targets BMI1⁺ CSCs to suppress cancer stemness and epithelial-mesenchymal transition (EMT) and elicits apoptosis to further potentiate Mn-based metalloimmunotherapy. Both <i>in vitro</i> and <i>in vivo</i> experiments elucidate that PMB NPs function as designed, exerting powerful immunotherapeutic and chemotherapeutic impacts to impede HNSCC growth and metastasis as well as bolster anti-PD-1-based ICB. Collectively, our findings provide a promising therapeutic strategy against HNSCC by combinational CSCs elimination and STING activation <i>via</i> metalloimmunotherapy.