Work

The Tumor–Platelet–Immune Interface: Driving Metastasis, Pre-Metastatic Niche Formation and Therapeutic Vulnerabilities

Year: 2026

Type: article

Abstract: 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.

Source: Expert Reviews in Molecular Medicine

DOI: 10.1017/erm.2026.10043