Takahiro Ochiya

Tumor tissue is densely packed with cancer cells, non‐cancerous cells, and ECM, forming functional structures. Cancer cells transfer extracellular vesicles (EVs) to modify surrounding normal cells into cancer‐promoting cells, establishing a tumor‐favorable environment together with other signaling molecules and structural components. Such tissue environments largely affect cancer cell properties, and so as EV‐mediated cellular communications within tumor tissue. However, current research on EVs focuses on functional analysis of vesicles isolated from the liquid phase, including cell culture supernatants and blood draws, 2D‐cultured cell assays, or systemic analyses on animal models for biodistribution. Therefore, we have a limited understanding of local EV transfer within tumor tissues. In this review, we discuss the need to study EVs in a physiological tissue context by summarizing the current findings on the impacts of tumor tissue environment on cancer EV properties and transfer and the techniques required for the analysis. Tumor tissue environment is likely to alter EV properties, pose physical barriers, interactions, and interstitial flows for the dynamics, and introduce varieties in the cell types taken up. Utilizing physiological experimental settings and spatial analyses, we need to tackle the remaining questions on physiological EV‐mediated cancer–host cell interactions. Understanding cancer EV‐mediated cellular communications in physiological tumor tissues will lead to developing interaction‐targeting therapies and provide insight into EV‐mediated non‐cancerous cells and interspecies interactions.