Tumors often engage the lymphatic system to invade and metastasize. The tumor-draining lymph node (dLN) may be an immune privileged site that protects the tumor from host immunity, and lymph flow draining tumors is often increased, enhancing communication between the tumor and the sentinel node. In addition to increasing transport of tumor antigens and regulatory cytokines to the lymph node, increased lymph flow in the tumor margin causes mechanical stress-induced changes in stromal cells that stiffen the matrix and alter the immune microenvironment of the tumor. In this proposed project, we will investigate the interplay between lymphatic drainage and flow-induced mechanotransduction in the tumor stroma that may synergize to promote tumor immune escape by appropriating lymphatic mechanisms of peripheral tolerance. We will address the hypothesis that lymphatic drainage and flow-induced mechanotransduction in the tumor stroma synergistically promote tumor immune escape by altering the immune microenvironment, and that targeting lymphatic drainage from the tumor may represent a new avenue for tumor immunotherapy. For the latter, we will develop strategies to limit or block lymphatic flow in the tumor microenvironment and characterize their ability to improve the efficacy of tumor immunotherapy by dampening local immunosuppression in the tumor stroma and tumor-draining lymph node (dLN). We will combine in vivo mouse models and intravital imaging with engineered in vitro microenvironments and nanoparticle-based targeting strategies in three broad aims designed to constitute several PhD and postdoctoral projects.