A Hybrid Manganese Nanoparticle Simultaneously Eliminates Cancer Stem Cells and Activates STING Pathway to Potentiate Cancer Immunotherapy

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 via 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 in vitro and in vivo 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 via metalloimmunotherapy.