Learning Objectives After completing this course, the reader will be able to: Discuss the role of TNF‐a in cancer survival and apoptosis. Describe the mechanism of chemotherapy potentiation by TNF‐a. Explain the selective targeting of tumor vasculature by TNF‐a. Discuss TNFR‐1 and TNFR‐2 signaling. Access and take the CME test online and receive 1 AMA PRA category 1 credit at http://CME.TheOncologist.com Tumor necrosis factor alpha (TNF‐α), isolated 30 years ago, is a multifunctional cytokine playing a key role in apoptosis and cell survival as well as in inflammation and immunity. Although named for its antitumor properties, TNF has been implicated in a wide spectrum of other diseases. The current use of TNF in cancer is in the regional treatment of locally advanced soft tissue sarcomas and metastatic melanomas and other irresectable tumors of any histology to avoid amputation of the limb. It has been demonstrated in the isolated limb perfusion setting that TNF‐α acts synergistically with cytostatic drugs. The interaction of TNF‐α with TNF receptor 1 and receptor 2 (TNFR‐1, TNFR‐2) activates several signal transduction pathways, leading to the diverse functions of TNF‐α. The signaling molecules of TNFR‐1 have been elucidated quite well, but regulation of the signaling remains unclear. Besides these molecular insights, laboratory experiments in the past decade have shed light upon TNF‐α action during tumor treatment. Besides extravasation of erythrocytes and lymphocytes, leading to hemorrhagic necrosis, TNF‐α targets the tumor‐associated vasculature (TAV) by inducing hyperpermeability and destruction of the vascular lining. This results in an immediate effect of selective accumulation of cytostatic drugs inside the tumor and a late effect of destruction of the tumor vasculature. In this review, covering TNF‐α from the molecule to the clinic, we provide an overview of the use of TNF‐α in cancer starting with molecular insights into TNFR‐1 signaling and cellular mechanisms of the antitumor activities of TNF‐α and ending with clinical response. In addition, possible factors modulating TNF‐α actions are discussed.

Traditionally, the goal of nanoparticle-based chemotherapy has been to decrease normal tissue toxicity by improving drug specificity to tumors. The EPR effect (Enhanced Permeability and Retention) can permit passive accumulation into tumor interstitium. However, suboptimal delivery is achieved with most nanoparticles because of heterogeneities of vascular permeability, which limits nanoparticle penetration. Further, slow drug release limits bioavailability. We developed a fast drug-releasing liposome triggered by local heat that has already shown substantial anti-tumor efficacy and is in human trials. Here, we demonstrate that thermally sensitive liposomes release doxorubicin inside the tumor vasculature. Real-time confocal imaging of doxorubicin delivery to murine tumors in window chambers and histologic analysis of flank tumors illustrates that intravascular drug release increases free drug in the interstitial space. This increases both the time that tumor cells are exposed to maximum drug levels and the drug penetration distance, compared with free drug or traditional pegylated liposomes. These improvements in drug bioavailability establish a new paradigm in drug delivery: rapidly triggered drug release in the tumor bloodstream.