<p>Up to 40% of cancer-related deaths are driven by lethal thromboinflammatory complications, highlighting the urgent need for strategies that disrupt the bidirectional interplay between coagulation and tumor progression. Platelets, long recognized for their hemostatic role, are now understood as active accomplices in metastasis, angiogenesis, immune evasion, and cancer-associated thrombosis. At the center of these processes is glycoprotein VI (GPVI), a platelet-specific receptor that mediates activation, degranulation, and aggregation in tumor response- and matrix-derived ligands. By sustaining circulating tumor cell survival and driving venous thromboembolism across multiple malignancies, GPVI emerges as a critical but underexploited therapeutic target. Preclinical studies show that GPVI blockade suppresses metastasis and thrombosis with minimal bleeding risk; however, translation is limited by the lack of precision delivery platforms and validated biomarkers for patient selection. To address these gaps, we propose a multifunctional, pH-sensitive nanoparticle engineered with anti-Vascular Cell Adhesion Molecule-1 (VCAM) ligands to home to tumor vasculature. Within the acidic tumor microenvironment, the system releases a synergistic payload of cytotoxic agents, GPVI antagonists, and immune checkpoint inhibitors. This approach dismantles the platelet “cloak,” interrupts platelet–tumor crosstalk, restores T cell and NK cell responses, and directly eliminates tumor cells, maximizing local efficacy while minimizing systemic toxicity. GPVI-targeted, nanoparticle-enabled therapy thus defines a new translational frontier in onco-hematology, achieving selective suppression of platelet-driven tumor progression and thrombosis without compromising hemostasis.</p>