Tumor-Associated Platelets Suppress T-cell Function and Promote Immune Evasion in TNBC via the P-selectin/P-selectin...

Tumor-associated platelets (TAP), 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 have shown promise, their efficacy is frequently limited by T-cell exhaustion and therapeutic resistance. In this study, 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 antitumor cytotoxicity. Using in vitro coculture 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 antitumor immunity and identify the P-selectin-PSGL-1 axis as a therapeutically actionable target to overcome resistance to immunotherapy in TNBC.

Tumor-associated platelets help TNBCs evade immune attack by suppressing T-cell function through P-selectin signaling. Blocking this pathway with crizanlizumab restores antitumor immunity and enhances response to immunotherapy, identifying a promising new combination treatment strategy for patients with this aggressive form of breast cancer.