Platelets as non-canonical immune regulatory nodes: orchestrating T cell dysfunction and immunotherapy resistance in cancer.

Immune checkpoint inhibitors (ICIs) have reshaped cancer treatment; however, durable clinical benefit remains limited by primary and acquired resistance, frequently associated with T cell dysfunction within an immunosuppressive tumor microenvironment. Beyond their classical role in hemostasis, platelets have emerged as active immune modulators capable of shaping antitumor T cell responses. Accumulating evidence indicates that platelets engage T cells through contact-dependent receptor-ligand interactions, immunomodulatory soluble factors, and the transfer of checkpoint-associated extracellular vesicles, thereby reinforcing dysfunctional T cell states and constraining responses to immune checkpoint blockade. In this review, we synthesize current mechanistic insights into platelet-T cell crosstalk, delineate its differential impact across T cell subsets, and integrate these processes into a broader framework of immune evasion and immunotherapy resistance. We further discuss emerging translational strategies aimed at modulating platelet immune functions, including antiplatelet drug repurposing, selective targeting of platelet-immune interfaces, and metabolic interventions to restore T cell fitness. Collectively, this work reframes platelets as non-canonical immune regulatory nodes and highlights platelet-T cell interactions as a therapeutically actionable layer of immune regulation with implications for improving and personalizing cancer immunotherapy.