Protrusion-Derived Extracellular Vesicles (PD-EVs) and Their Diverse Origins: Key Players in Cellular Communication, Cancer Progression, and T Cell Modulation

Protrusion-derived extracellular vesicles (PD-EVs) are a specialized subset of extracellular vesicles (EVs) generated from dynamic cellular extensions. These structures play a crucial role in cellular communication and have emerged as pivotal mediators in various biological processes, including cancer progression and immune modulation. In cancer, PD-EVs facilitate tumor growth, invasion, and metastasis by delivering oncogenic cargo that remodels the tumor microenvironment, promotes angiogenesis, and supports immune evasion. They are also implicated in establishing pre-metastatic niches and enabling cancer cells to colonize distant organs. PD-EVs are characterized by a distinct molecular signature linked to their origin from specialized plasma membrane domains. Their unique composition makes them promising biomarkers for early cancer detection, disease monitoring, metastatic potential assessment, and therapeutic response evaluation. Targeting PD-EV biogenesis, release, or uptake represents a novel therapeutic strategy to disrupt tumor progression and overcome resistance to current treatments. However, distinguishing PD-EVs from other EV subtypes remains challenging due to overlapping characteristics. This review consolidates the latest evidence on PD-EVs, focusing on their biogenesis, limitations in their study, functional roles in cancer, and potential applications in diagnostics and therapeutics, especially concerning immune modulation and T-cell activation.