Triple-negative breast Cancer (TNBC) disproportionately affects young women with a survival median of only 1-1.5 years after the diagnosis. The short survival time in diagnosed patients is attributed to the early occurrence of metastases, where there is evidence of lung metastases in 37% of cases. Understanding how to disrupt TNBC metastatic initiation or halt the growth of existing lung metastases is crucial for preventing premature death. Unfortunately, the lack of targeted therapies for TNBC leaves chemotherapy as the main line of treatment, which shows modest results for patients with metastases. Emerging data suggest that the JNK pathway, a stress-activated molecular pathway in TNBC cells, increases both metastatic shedding from the primary tumor and survival in the lung microenvironment. JNK+ TNBC cells communicate with macrophages, endothelial cells, and fibroblasts, forming essential cross-talks that drive metastasis initiation and growth. Because chemotherapy itself activates JNK, disrupting these cross-talks is crucial for more effective therapies. Targeting single molecular components of the JNK–macrophage–vasculature or tumor–fibroblast axes in mouse xenograft models has not eliminated metastases. Direct JNK pathway inhibition also failed to fully prevent the metastatic disease, although it suppressed tumor–fibroblast signaling, reduced extracellular matrix remodeling, enhanced chemotherapy response, and limited macrophage activation. Notably, the timing of JNK inhibition (before tumor cell injection, before chemotherapy, or concurrent with chemotherapy) produced variable outcomes in metastasis number, size, and growth. To capture metastases initiation and growth dynamics, we developed an agent-based model (ABM) of TNBC–lung microenvironment ecosystem interactions. The ABM recapitulates spatiotemporal changes in TNBC tumor cells’ proliferation/death and the growth dynamics of macrophages, endothelial cells, and fibroblasts. Model predictions of the metastatic growth were validated against spatial distributions and proliferation patterns of JNK+ cells in short-term (7–10 day) mouse xenografts and compared with longer-term experimental data. Using eco-evolutionary insights from the ABM, we optimized treatment strategies aimed at disrupting tumor–lung microenvironment interactions. Results show that therapeutic success depends strongly on the sequence and spatial context of JNK+ tumor cell–lung interactions during metastatic initiation. Our ongoing work leverages this modeling framework to identify interventions capable of systematically reducing or eradicating long-term metastatic burden. While developed for TNBC, this approach provides a broadly applicable framework for studying metastatic niche ecology and guiding treatment optimization in other cancers.