Platelets in the tumor microenvironment: potential mediators of immune exclusion and resistance to immune checkpoint inhibitor therapy

Cancer cells employ diverse strategies to evade immune surveillance and resist therapy, including immune exclusion—a phenomenon where cytotoxic T cells fail to infiltrate the tumor microenvironment (TME), severely limiting immune checkpoint inhibitor (ICI) efficacy. Emerging evidence suggests that platelets, traditionally known for their role in hemostasis, may act as key players within the TME. This review introduces a novel perspective on tumor-infiltrating platelets (TIPs) as potential orchestrators of immune exclusion, linking them to the six Delphi-defined criteria, which were established through international cancer experts based on modified consensus Delphi process: lack of chemotactic factors, immunosuppressive cytokines, specific cancer-associated fibroblast (CAF) subtypes, mechanical barriers, disordered vasculature, and increased T-cell apoptosis. We further explore TIP-mediated contributions to related features, such as epithelial-mesenchymal transition (EMT), M2 macrophage polarization, and CXCL12 signaling, which exacerbate exclusion and promote metastasis. Through integration of mechanistic studies and pan-cancer TCGA analyses, we reveal that TIPs exhibit significant, yet heterogeneous, correlations with immune exclusion features across diverse solid tumors. By elucidating these mechanisms, this review underscores the potential role of TIPs as promising therapeutic targets to dismantle immune barriers, enhance ICI responses, and curb metastasis, advocating for platelet-targeted combinations in future immunotherapy trials.