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

Area of Science:

• Oncology
• Nanotechnology
• Immunotherapy

Background:

• Immunotherapies like immune checkpoint blockades (ICBs) show limited efficacy in head and neck squamous cell carcinoma (HNSCC).
• Therapeutic-refractory cancer stem cells (CSCs) and insufficient cyclic guanosine monophosphate-adenosine monophosphate synthase/interferon gene stimulator (cGAS/STING) pathway activation contribute to immune evasion and treatment resistance in HNSCC.

Purpose of the Study:

• To develop a nanocomplex for HNSCC therapy that simultaneously eradicates CSCs and activates the STING pathway.
• To create a novel nanoparticle formulation for enhanced HNSCC treatment.

Main Methods:

• Synthesized PTC209/MnO2@BSA (bovine serum albumin) nanoparticles (PMB NPs) using a green process.
• Investigated the role of released manganese (Mn) ions in enhancing cGAS-STING signaling and dendritic cell maturation.
• Assessed the targeting of BMI1+ CSCs by released PTC209 to suppress stemness, epithelial-mesenchymal transition (EMT), and induce apoptosis.
• Evaluated the efficacy of PMB NPs both in vitro and in vivo.

Main Results:

• PMB NPs effectively release Mn ions in an acidic tumor microenvironment, boosting cGAS-STING signals and promoting T-cell responses.
• PTC209 release suppressed CSC stemness and EMT, inducing apoptosis and potentiating Mn-based metalloimmunotherapy.
• PMB NPs demonstrated significant therapeutic effects, inhibiting HNSCC growth and metastasis.
• Combined therapy using PMB NPs and anti-PD-1 ICB showed enhanced anti-tumor activity.

Conclusions:

• PMB NPs offer a promising strategy for HNSCC treatment by combining CSC elimination and STING activation via metalloimmunotherapy.
• This approach enhances the efficacy of existing immunotherapies like anti-PD-1 ICB.
• The developed nanoparticles represent a novel therapeutic avenue for overcoming HNSCC resistance.