Targeting PDPN enhances antitumor T-cell activity by disrupting β-catenin-mediated PD-L1 expression in melanoma.

Introduction: Melanoma is a highly immunogenic and aggressive malignancy characterized by pronounced intratumoral lymphocytic infiltration and significant responsiveness to immunotherapeutic interventions. The oncogenic glycoprotein podoplanin (PDPN) is commonly overexpressed in various cancer types, where it facilitates metastatic dissemination through interactions with CLEC-2 on platelets and other stromal cells, thereby contributing to stromal immunosuppression. Although the protumoral roles of PDPN are well documented, its precise mechanistic contributions to immune evasion in melanoma remain only partly defined and require further elucidation. Methods: To clarify the immunological role of PDPN in melanoma, multiplex immunofluorescence staining was performed on human tissue microarrays, and bioinformatic analyses were conducted to determine the associations of PDPN with PD-L1 expression and CD8 Results: Multi-omics analyses indicated that PDPN expression is highly correlated with immune checkpoint markers, most notably PD-L1 (r = 0.504, p < 0.001), and displays an inverse relationship with the infiltration of intratumoral cytotoxic immune cells. Single-cell and spatial transcriptomic profiling revealed that PDPN supports the exclusion of CD8 Discussion: These findings identify PDPN as a critical driver of immune evasion in melanoma via b-catenin-mediated PD-L1 upregulation. Inhibitory targeting of PDPN with CY12-RP2 represents a promising therapeutic approach capable of disrupting this immunosuppressive pathway and reversing tumor immune escape.