SAICAR Drives T Regulatory Cell Differentiation and FOXP3 Maintenance to Promote Immunotherapy Resistance

Area of Science:

• Immunology
• Metabolic pathways
• Cancer research

Background:

• Regulatory T cells (Tregs) in the tumor microenvironment limit anti-PD-1 therapy effectiveness.
• Metabolic reprogramming is crucial for anti-tumor immunity, yet specific Treg metabolic drivers in cancer remain unclear.

Purpose of the Study:

• To identify metabolic cues programming Treg differentiation in cancer.
• To investigate the role of SAICAR in Treg induction and anti-PD-1 resistance.

Main Methods:

• Identified SAICAR as a key metabolite.
• Investigated SAICAR's mechanism involving PPM1A and SMAD3 signaling.
• Analyzed SAICAR levels in human tumors and mouse models.
• Assessed the impact of SAICAR reduction on antitumor immunity and PD-1 blockade efficacy.
• Evaluated 6-mercaptopurine's effect on SAICAR-driven immunosuppression.

Main Results:

• SAICAR was identified as a key driver of Treg induction and resistance to PD-1 blockade.
• SAICAR inhibits PPM1A, sustaining TGF-β-SMAD3 signaling and FOXP3 transcription, thereby stabilizing Tregs.
• Elevated intratumoral SAICAR correlates with increased Tregs, suppressed effector T cells, and PD-1 blockade failure.
• Reducing SAICAR restored antitumor immunity and sensitized tumors to PD-1 therapy.
• Low-dose 6-mercaptopurine synergized with anti-PD-1 therapy by disrupting SAICAR-driven immunosuppression without systemic toxicity.

Conclusions:

• SAICAR is a critical immunometabolic regulator linking purine metabolism to immune evasion in cancer.
• Targeting SAICAR presents a therapeutically actionable strategy to overcome metabolite-driven resistance to immune checkpoint blockade.
• SAICAR inhibition offers a promising approach to enhance anti-PD-1 immunotherapy efficacy.