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

Regulatory T (Treg) cells within the tumor microenvironment critically undermine the efficacy of PD-1 immune checkpoint blockade. Metabolic reprogramming has emerged as a critical determinant of antitumor immunity, highlighting the need to define the metabolic cues that program Treg differentiation in cancer. In this study, we identified the purine biosynthesis intermediate succinylaminoimidazole carboxamide ribose-5'-phosphate (SAICAR) as a key metabolic driver of Treg induction and resistance to anti-PD-1 immunotherapy. Mechanistically, SAICAR directly bound to the serine/threonine phosphatase PPM1A, inhibiting SMAD3 dephosphorylation and thereby sustaining TGFβ-SMAD3 signaling. Persistent SMAD3 activation enhanced FOXP3 transcription and stabilized the Treg lineage. In both human tumors and mouse models, elevated intratumoral SAICAR levels were associated with increased Treg accumulation, suppression of effector T-cell function, and failure of PD-1 blockade. Genetic or pharmacologic reduction of SAICAR restored antitumor immunity and sensitized tumors to PD-1 therapy. Notably, low-dose 6-mercaptopurine disrupted SAICAR-driven immunosuppression and synergized with anti-PD-1 treatment without inducing systemic immune toxicity. Together, these findings establish SAICAR as an immunometabolic regulator that links purine metabolism to immune evasion and highlight a therapeutically actionable pathway to overcome metabolite-driven resistance to immune checkpoint blockade. SIGNIFICANCE: SAICAR is necessary and sufficient to drive Treg-mediated immunosuppression in the tumor microenvironment, linking tumor metabolism and immunosuppression and providing mechanistic insights for metabolism-guided combination immunotherapy.