(2) Tumor microenvironmental cues—hypoxia in ESCC induces Piezo1-mediated calcium influx, triggering PYK2 phosphorylation at Y402 and subsequent NOX5/c-Abl complex assembly to fuel tumor progression (16, 42); whereas in GC, mechanical stress from peristalsis may modulate RhoA-ROCK signaling through PYK2-p190RhoGEF crosstalk, potentially influencing cell detachment dynamics (43, 44). Here, NOX5 is linked to esophageal squamous cell carcinoma.