Introduction: Elevated tumor interstitial fluid pressure (TIFP) is a major barrier to successful cancer treatment. It is mainly caused by an inadequate tumor perfusion resulting from missing lymphatic vessels, a leaky and immature tumor vasculature, an overly stimulated angiogenesis, and interstitial fibrosis. TIFP hampers convection-driven fluid transport within tumors and causes inefficient penetration and distribution of anti-neoplastic drugs.Areas covered: This review covers mechanisms and regulation of TIFP and gives an overview of strategies to overcome this barrier.Expert opinion: Increased TIFP occurs in vivo and hence may be overlooked in molecular biology-driven cancer research. Its pervasiveness means that it can reduce the effectiveness of anti-neoplastic drugs. This is often misinterpreted as drug resistance; it precedes all drug resistance mechanisms operating at the cell level. The key challenge in the field of cancer therapeutics is to find ways to lower TIFP. Several drug therapies have been tried but none of them have had an impact in the clinic. This is an overarching problem in the field of cancer research.
Keywords: Cancer biology; chemotherapy; convection; drug resistance; extracellular matrix; interstitial fluid pressure; tissue hypoxia; tissue transport.