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The Tumor–Platelet–Immune Interface: Driving Metastasis; Pre-Metastatic Niche Formation and Therapeutic Vulnerabilities
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DOI：10.1017/erm.2026.10043.png)
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Abstract
En 中文
Metastatic dissemination remains the leading cause of cancer-related mortality; driven not only by tumor-intrinsic factors but also by dynamic interactions within the tumor microenvironment (TME). Platelets and leukocytes orchestrate a systemic pro-metastatic network by shielding circulating tumor cells (CTCs); inducing neutrophil extracellular trap (NET) formation; and remodeling the extracellular matrix to prime pre-metastatic niches. This platelet-leukocyte crosstalk simultaneously promotes immune evasion; thromboinflammation; and metastatic seeding; creating a multi-cellular; temporally coordinated program that conventional anti-platelet and anti-inflammatory therapies inadequately target. Here; we propose a next-generation; multi-stimuli-responsive nanoparticle platform designed to disrupt these interconnected metastatic circuits. Engineered to respond to acidic pH in primary tumors and matrix metalloproteinases in pre-metastatic niches; these nanoparticles enable spatiotemporally controlled release of cytotoxic agents; anti-platelet drugs; and immune checkpoint inhibitors. Surface functionalization with anti-P-selectin further enhances specificity to tumor vasculature and facilitates platelet ‘hitchhiking’ for targeting CTCs. By simultaneously neutralizing platelet-leukocyte interactions; inhibiting NET-mediated scaffolds; and restoring anti-tumor immunity; this integrated strategy addresses multiple pro-metastatic mechanisms in a coordinated fashion. This work provides a conceptual and translational framework for precision anti-metastatic therapeutics; transforming the paradigm from single-pathway interventions to network-targeted strategies that disrupt tumor progression; CTC survival and metastatic niche formation. Our approach represents a critical step toward actionable; multi-modal interventions capable of preventing metastatic disease.
Keywords:
circulating tumor cells
enzyme- and pH-sensitive nanoparticle
hydrogel
neutrophil extracellular traps
platelet-leukocyte crosstalk
pre-metastatic niche
tumor microenvironment
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