PTPN22 Dephosphorylates CBL to Inhibit PD-L1 Ubiquitination and Drive Immunosuppression in Renal Cell Carcinoma

High lymphocyte infiltration and T cell exhaustion characterize the tumor microenvironment in renal cell carcinoma (RCC). Protein tyrosine phosphatase N22 (PTPN22), a protein tyrosine phosphatase that mediates proteins tyrosine dephosphorylation, is a negative regulator of T cell receptor signaling, but its role in tumor cells has been underappreciated. PTPN22 is highly expressed in RCC cells and positively correlated with PD-L1 protein expression. CBL was newly identified as a substrate of PTPN22, and our study reveals for the first time that CBL mediates the K48-linked ubiquitination of PD-L1. PTPN22 specifically interacts with CBL, catalyzing the dephosphorylation of tyrosine 700 and inhibiting CBL binding to PD-L1, thereby preventing CBL-mediated ubiquitination and degradation of PD-L1. This stabilization of PD-L1 promotes T cell exhaustion and immunosuppression. Through screening of traditional Chinese medicine monomers, we identified curcumin as a potential PTPN22 inhibitor. Curcumin reduces PTPN22 stability and PTPN22 expression by directly binding to PTPN22. <i>In vivo</i> experiments demonstrated that combining curcumin with immune checkpoint inhibition (ICIs) further promotes T cell activation, inhibits Tregs infiltration, and enhances ICIs efficacy against tumor growth. Therefore, PTPN22 represents a therapeutic target for improving T cell exhaustion in RCC and enhance ICIs efficacy through CBL-mediated ubiquitination and degradation of PD-L1.