<p>Systemic chemotherapy often affects cells beyond the tumor, raising concerns about their impact on peripheral tissues, including the central nervous system (CNS). The meningeal lymphatics drain cerebrospinal fluid from the CNS to the deep cervical lymph nodes, assisting in immunosurveillance and linking the CNS to the periphery. They have been implicated in a number of brain-related disorders with disruption exacerbating cognitive deficits. However, in vivo, distinguishing between direct and indirect effects of systemic chemotherapy on the meningeal lymphatics remains highly challenging, making it difficult to isolate specific impact on the CNS. To address this, we present two models we have developed that allow the examination of cellular and tissue-level changes to study the effects of systemic chemotherapy on the meningeal lymphatics. Our in vitro tissue engineered model representative of a meningeal lymphatic vessel lumen shows cell disruption, while our ex vivo model culturing mouse meningeal layers probes structural changes in a controlled setting. Finally, we correlate functional outcomes with observed changes in vivo and show that systemic taxane chemotherapy leads to morphological changes in the meningeal lymphatics, a trend of reduced flow through the brain, and impaired cognition, emphasizing the need for further study of off-target impacts in the CNS and the value of multi-model approaches.</p><p></p>