The PTPN22-CBL-PD-L1 axis represents a clinically targetable resistance mechanism in RCC, with dual implications: (1) PTPN22 expression may serve as a biomarker for ICI response stratification, and (2) pharmacological inhibition of this pathway (e.g., via curcumin derivatives) could overcome resistance to existing immunotherapies. The gene discussed is PTPN22; the disease is renal cell carcinoma.