Targeting STING Signalling Polarizes Tumor-Associated Neutrophils to Boost Anticancer and Abscopal Antimetastatic...

Area of Science:

• Immunology
• Cancer Biology
• Pharmacology

Background:

• The stimulator of interferon genes (STING) pathway is a key target in cancer immunotherapy.
• Tumor-associated neutrophils (TANs) play a critical role in cancer progression and immune response.
• TANs exist in antitumor (N1) and tumor-supportive (N2) subtypes, influencing therapeutic outcomes.

Purpose of the Study:

• To determine if STING activation can repolarize TANs towards the anti-cancer N1 subtype.
• To investigate the role of STING-activated TANs in cancer metastasis.
• To assess the impact of STING activation on macrophage polarization.

Main Methods:

• Murine melanoma (B16-F10) and breast carcinoma (4T1) models were used.
• Flow cytometry, immunofluorescence microscopy, and multiplex immunoassay analyzed TAN phenotypes.
• Magnetic cell sorting assessed TAN cytotoxicity, and metastasis models evaluated STING agonist effects.

Main Results:

• STING targeting shifted TAN polarization to the N1 subtype, increasing expression of ICAM-1, CD69, Fas, CXCL10, TNFα, CCL3, and decreasing VEGF.
• STING activation induced TAN cytotoxicity against 4T1 cancer cells and inhibited primary tumor metastasis.
• Treatment led to lung immune cell conversion towards an anti-cancer phenotype and polarized bone marrow-derived macrophages (BMDM) towards M1-like cells.

Conclusions:

• Targeting the STING pathway effectively polarizes TANs towards an anti-cancer N1 phenotype.
• This study elucidates the role of STING-activated TANs in combating metastasis and influencing macrophage polarization.
• Findings provide crucial insights into STING-activating therapy's impact on TAN functions and the tumor microenvironment.