Platelet-Mediated Suppression of T Cell Function Drives Immune Evasion in Triple Negative Breast Cancer through the P-Selectin / PSGL-1 Pathway

Abstract

Immune checkpoint inhibitors (ICIs) have demonstrated clinical promise in triple-negative breast cancer (TNBC), yet their effectiveness is often limited by acquired resistance and immune refractoriness. This underscores the urgent need to improve strategies that restore or enhance anti-tumor immunity. Platelets--long recognized for their role in hemostasis--have emerged as key immunomodulators in cancer by interacting with circulating tumor cells, shielding them from sheer stress and immune clearance while actively promoting immune evasion. Here, we uncover a previously unrecognized immunoregulatory pathway whereby platelet-derived P-selectin engages P-selectin glycoprotein ligand-1 (PSGL-1) on T cells, triggering immunosuppressive signaling and promoting T-cell exhaustion. This interaction, identified using in vitro co-culture systems and validated in in vivo mouse models of TNBC, reveals a targetable form of platelet-mediated immune suppression that contributes to ICI resistance. PSGL-1, traditionally known for mediating leukocyte trafficking, functions here as an immune checkpoint receptor, further underscoring the therapeutic relevance of this axis. Together, our findings highlight the P-selectin-PSGL-1 interaction as a novel and targetable mechanism of immune evasion and provide preclinical evidence that its disruption may enhance ICI responsiveness and improve outcomes in TNBC. Key PointsO_LITumor-associated platelets (TAPs) exhaust T-cells through P-selectin/P-selectin glycoprotein ligand-1 binding C_LIO_LIPharmaceutical blockade of P-selectin using Crizanlizumab, prevents exhaustion and allows T-cell function C_LI