5-Fluorouracil efficacy requires anti-tumor immunity triggered by cancer-cell-intrinsic STING

Area of Science:

• Immunology
• Oncology
• Pharmacology

Background:

• 5-Fluorouracil (5-FU) is a cornerstone chemotherapy, but its in vivo efficacy mechanisms in immunocompetent hosts are not fully understood.
• The role of intrinsic cancer cell immunity in mediating 5-FU response requires further elucidation.

Purpose of the Study:

• To investigate the mechanisms by which 5-Fluorouracil (5-FU) exerts its anti-tumor effects in vivo.
• To determine the role of STING (stimulator of interferon genes) pathway activation in cancer cells during 5-FU treatment.

Main Methods:

• Modeling 5-FU response in murine colon and melanoma tumor models.
• Assessing the impact of STING and cGAS (cyclic GMP-AMP synthase) deficiency on 5-FU efficacy.
• Evaluating the role of type I interferon production and sensing.
• Analyzing intratumoral T cell infiltration and the effect of T-cell depletion.
• Correlating STING expression with patient survival and chemotherapy response in human colorectal cancer specimens.

Main Results:

• Effective 5-FU tumor burden reduction in vivo is dependent on cancer-cell-intrinsic STING activation and subsequent type I interferon production.
• Loss of STING in cancer cells necessitates higher 5-FU doses for tumor reduction, highlighting its importance in vivo but not in vitro.
• 5-FU treatment increases intratumoral T cells, and T-cell depletion abrogates 5-FU efficacy.
• Higher STING expression in human colorectal tumors correlates with improved survival and chemotherapy response.

Conclusions:

• 5-Fluorouracil (5-FU) efficacy relies on triggering cancer cell-intrinsic STING-mediated anti-tumor immunity.
• The STING-IFN pathway in cancer cells and IFN-sensing by immune cells are critical for 5-FU response.
• Findings suggest strategies to enhance 5-FU therapeutic effectiveness and reduce toxicity by targeting the STING pathway.