Hypoxia orchestrates the lymphovascular–immune ensemble in cancer

The lymphatic system is a major component of the tumor microenvironment, wherein lymphovascular remodeling occurs as a response to low O2 (hypoxia), resulting in metastatic dissemination and patient mortality. Further to this notion, recent data have brought forth an expanded view of lymphatics, beyond a 'passthrough' system for cancer cells (CCs) onto an immune effector function, crucially determining targeted (immuno)therapeutic responses. We hereby provide a novel view of how hypoxia-driven mechanisms of lymphatic remodeling and immunotolerance can be actively co-opted by CCs tilting the immunological balance away or in favor of suppressive tumor and metastatic microenvironments. We hypothesize that specific combinatorial approaches targeting hypoxia signaling pathways might be utilized to reverse this imbalance, to amplify responses to targeted immunotherapies for patients with cancer.