From escort to target, the multidimensional roles and prospects of platelets in tumor immune checkpoint inhibitor therapy

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy by reinvigorating antitumor immunity through the blockade of inhibitory pathways such as programmed cell death protein 1 (PD-1)/programmed cell death protein ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Despite their remarkable clinical success, only a subset of patients derives durable benefit, whereas others exhibit primary or acquired resistance and develop immune-related adverse events (irAEs). These heterogeneous responses highlight an urgent need for robust biomarkers to predict therapeutic efficacy and for innovative combinatorial strategies to enhance clinical outcomes. Beyond their classical roles in hemostasis and thrombosis, platelets have recently emerged as pivotal modulators of tumor progression and immune regulation. Accumulating evidence indicates that platelets engage in dynamic crosstalk with tumor and immune cells, reshaping the tumor microenvironment (TME) and modulating the response to ICI therapy. Of note, platelet-associated immune checkpoint molecules (e.g., PD-L1) have shown great promise as liquid biopsy markers for patient stratification and real-time immunomonitoring. Furthermore, platelet-associated nucleic acids and traditional platelet parameters (such as platelet count and activation status) have been identified as accessible and effective biomarkers for predicting ICI responsiveness and irAEs. These platelet-derived components may also represent novel therapeutic targets to overcome resistance and potentiate ICI efficacy. Meanwhile, advances in biomaterials and genetic engineering have further enabled the development of platelet-based and platelet membrane (PM)-camouflaged delivery systems endowed with tumor-homing capacity, combinatorial drug delivery potential, and immune-responsive release properties. Collectively, these insights reposition platelets from passive participants to active regulators and versatile therapeutic platforms in cancer immunotherapy, providing a conceptual foundation for next-generation platelet-guided precision immunotherapeutic strategies.