The clinical and molecular significance associated with STING signaling in breast cancer

Area of Science:

• Oncology
• Immunology
• Pathology

Background:

• STING signaling is vital for anti-cancer treatment response.
• Current methods for measuring STING activation in cancer are insufficient.

Purpose of the Study:

• To develop and validate a novel immunohistochemistry-based assay for assessing STING activation in tumor cells.
• To investigate the prognostic role of STING activation, specifically perinuclear STING (pnSTING), in estrogen receptor-positive (ER+) and ER- breast cancer.

Main Methods:

• Development of an immunohistochemistry assay for STING detection.
• Digital pathology assessment of STING localization (perinuclear vs. diffuse).
• Correlation of pnSTING expression with clinicopathological features, immune cell infiltration, and gene expression signatures in ER+ and ER- breast cancer.

Main Results:

• Perinuclear STING (pnSTING) expression in ER+ breast cancer is an independent predictor of good prognosis.
• High pnSTING correlates with increased immune cell infiltration and immune checkpoint upregulation in ER+ tumors.
• Low pnSTING in ER+ tumors is linked to immunosuppression, M2 macrophage infiltration, chromosomal instability, MYC amplification, and mTOR signaling, predicting poor prognosis.
• pnSTING did not show a significant prognostic role in ER- breast cancer, with STING signaling uncoupled from interferon responses.

Conclusions:

• The developed assay provides a robust method for measuring STING activation in cancer.
• pnSTING serves as a valuable prognostic biomarker in ER+ breast cancer, differentiating between immune-activated and immunosuppressed tumors.
• Identifying tumors with low pnSTING highlights potential therapeutic strategies targeting chromosomal instability, MYC, and mTOR pathways for improved patient outcomes.