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

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.