Tumor-Associated Platelets Suppress T-Cell Function and Promote Immune Evasion in TNBC via the P-selectin/ P-selectin glycoprotein ligand-1 Pathway

Tumor-associated platelets (TAPs), which are reprogrammed by tumor-derived signals to acquire immunosuppressive properties, represent an emerging mechanism of immune evasion in triple-negative breast cancer (TNBC). Although immune checkpoint inhibitors (ICIs) have shown promise, their efficacy is frequently limited by T cell exhaustion and therapeutic resistance. Here, we demonstrate that TAPs, unlike healthy circulating platelets, induce T cell dysfunction through platelet-derived P-selectin, which engages P-selectin glycoprotein ligand-1 (PSGL-1) on T cells. This interaction promotes immunosuppressive signaling, driving T cell exhaustion and impairing anti-tumor cytotoxicity. Using in vitro co-culture systems and in vivo TNBC models, we show that disruption of the P-selectin-PSGL-1 axis, including pharmacologic blockade with the FDA-approved anti-P-selectin antibody Crizanlizumab, restores T cell function and enhances responsiveness to immune checkpoint blockade. Notably, PSGL-1, traditionally recognized for its role in leukocyte trafficking and immune regulation, is co-opted by TAPs to suppress T cell activity, revealing a mechanism of platelet-mediated immune modulation. These findings establish TAPs as active regulators of anti-tumor immunity and identify the P-selectin-PSGL-1 axis as a therapeutically actionable target to overcome resistance to immunotherapy in TNBC.