Profilin-1 Deficiency Activates STING to Drive T Cell-Mediated Anti-Tumor Immunity in Breast Cancer

Area of Science:

• Cancer Biology
• Immunology
• Molecular Biology

Background:

• Dysregulation of actin-binding protein Profilin-1 (Pfn1) impacts tumor progression.
• The influence of Pfn1 on cancer immune surveillance is largely unknown.

Purpose of the Study:

• To investigate the role of Pfn1 in breast cancer immune surveillance.
• To determine if Pfn1 modulation in tumor cells affects anti-tumor immunity.

Main Methods:

• Utilized CRISPR/Cas9 knockout models in breast cancer cells.
• Assessed genomic instability, DNA repair defects, and cGAS-STING pathway activation.
• Employed immunocompetent mouse models to evaluate tumor regression and immune cell infiltration.

Main Results:

• Pfn1 depletion induced genomic instability, DNA repair defects, and cytosolic DNA accumulation.
• Activated the cGAS-STING pathway, leading to type I interferon (IFN) response and chemokine upregulation.
• Pfn1 loss promoted CD8+ T cell infiltration and robust tumor regression in vivo, dependent on an intact immune system.

Conclusions:

• Pfn1 loss in tumor cells activates a type I IFN response, driving T cell-mediated anti-tumor immunity.
• Targeting Pfn1-driven pathways offers potential therapeutic strategies to improve breast cancer immunotherapy outcomes.
• This study establishes a framework for how actin cytoskeletal protein dysregulation can enhance anti-tumor immune responses.