Mechanistic model of STIM-IP3R crosstalk in regulating breast cancer cell migration. Breast cancer cell migration is regulated by a dynamic interplay between STIM proteins and IP3Rs, which together shape the spatiotemporal pattern of intracellular Ca²⁺ signaling. In WT cells, transient ER Ca²⁺ depletion triggered by localized IP3R-mediated Ca²⁺ release is rapidly replenished through SOCE, driven by the coordinated activity of both STIM1 and STIM2. This balance of spatiotemporally separated localized Ca²⁺ signals from both IP3Rs and SOCE supports efficient cell migration. In cells lacking either STIM1 or STIM2, the remaining isoform functions near its activation threshold due to lower ER Ca²⁺ stores. As a result, even slight ER Ca²⁺ depletion, such as that initiated by IP3R activity, activates the residual STIM protein, shifting IP3R-mediated Ca²⁺ signals from localized to diffuse/global Ca²⁺ release mode. This altered Ca²⁺ pattern disrupts the finely tuned signaling required for cell migration, leading to impaired motility. In cells lacking both STIM isoforms, this feedback mechanism is lost entirely, allowing IP3Rs to continue generating localized Ca²⁺ signals unmodulated by STIM proteins. Restoration of spatially confined Ca²⁺ signaling supports the maintenance of cell migration despite the complete loss of STIM-mediated SOCE. Created with https://BioRender.com.