Targeting Purine Metabolism With 6‐Mercaptopurine Overcomes Solute Carrier Family 7 Member 2 Deficiency‐Induced Cisplatin Resistance in Tongue Squamous Cell Carcinoma

BACKGROUND: Cisplatin resistance remains a major clinical obstacle in the treatment of tongue squamous cell carcinoma (TSCC). Solute carrier family 7 member 2 (SLC7A2) is a key cationic amino acid transporter, yet its functional significance in TSCC drug resistance has not been explored. METHODS: We established cisplatin-resistant TSCC cell lines and performed integrated proteomics and metabolomics. SLC7A2 function was assessed via gain-of-function and loss-of-function assays combined with CCK-8, Transwell, wound healing, flow cytometry, Western blot, and RT-qPCR. RESULTS: SLC7A2 was markedly downregulated in both TSCC tissues and cisplatin-resistant cells. Multi-omics analysis revealed significant perturbations in purine metabolism, identifying 6-mercaptopurine (6-MP) as a critical metabolite. SLC7A2 overexpression or combined Cis+6-MP treatment synergistically suppressed proliferation, migration, and invasion while promoting apoptosis. Mechanistically, SLC7A2 expression correlated with p53 signaling activity: SLC7A2 knockdown increased MDM2 expression and induced cisplatin resistance, while SLC7A2 overexpression or Cis+6-MP treatment reversed these effects. Pharmacological inhibition of p53 with PFT-α sensitized cells to cisplatin, whereas p53 activation with Nutlin-3a partially reversed resistance in a p53-dependent manner. CONCLUSION: This study identifies SLC7A2 as a regulator of cisplatin response in TSCC, acting through the p53 signaling network. It also highlights 6-MP as a sensitizer, offering a combination strategy to overcome chemoresistance.