Do Metastatic Cells Arise from PD-L1⁺ Cell Niches in Gastric Adenocarcinoma?

Gastric cancer (GC), one of the most common malignancies worldwide, is strongly linked to metastasis, significantly worsening prognosis and survival rates. Metastasis initiation relies on epithelial cells undergoing an epithelial-mesenchymal transition and on an abnormal, leaky vasculature. Although the tumor cells involved in the metastatic process have a progression-associated gene signature associated with extracellular matrix organization and the epithelial-to-mesenchymal transition, they must originate from an immune-evasive ecosystem that allows tumors to hinder or evade immune surveillance, either by secreting immunosuppressive chemicals, recruiting regulatory immune cells, or expressing negative stimulatory immune checkpoint molecules such as PD-L1. Although the mechanism underlying the so-called "metastatic cascade" is beginning to emerge, the tumor microenvironment, or niche, in which metastatic cells arise, remains unknown. In this review, we speculate that the epithelial-mesenchymal transition generates PD-L1-expressing cancer stem cells within the primary tumor, which can form tumor niches that serve as sources of metastatic cells within the gastric adenocarcinoma microenvironment. Understanding the regulatory pathways governing metastasis may offer new avenues for developing more effective therapeutic approaches.