Editors' ChoiceCancer

Targeting the Tumor Microenvironment

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Science Translational Medicine  11 Nov 2009:
Vol. 1, Issue 6, pp. 6ec21
DOI: 10.1126/scitranslmed.3000560

One bull’s eye for cancer drugs is the tumor microenvironment, and Kortylewski et al. now show that a modified small interfering RNA (siRNA) might be the arrow. The cells that envelop a tumor participate in two processes that turn a tumor toxic—angiogenesis and metastasis—making these cells attractive therapeutic targets.

Killing tumor cells is one of the jobs of the immune system, but the composition of the tumor microenvironment wreaks havoc with tumor suppression by its paucity of tumor-specific T cells and its overabundance of other cells that manufacture compounds that stimulate angiogenesis and metastasis. In this study, the authors used siRNAs to target the oncogenic immune-suppressive transcription factor Stat3, which orchestrates this microenvironment mayhem. siRNAs are highly selective when it comes to their targets, but the pointed delivery of these agents to a specific physiological location can be tricky. These researchers outsmarted the system by tacking an oligonucleotide agonist of Toll-like receptor 9 (TLR9) onto an siRNA that stifles Stat3 gene expression. When this multifunctional reagent was injected into mice intravenously or at the tumor site, it entered tumor-hugging immune cells via TLR9 and silenced Stat3 expression. This action provoked a cascade that ultimately stimulated tumor-destroying immune responses. The authors have begun experiments to assess the utility of their TLR9-targeting siRNA in clinical situations. The fact that TLR9 decorates the membranes of only selected human immune cells suggests that this therapeutic approach would display a high degree of specificity.

M. Kortylewski et al., In vivo delivery of siRNA to immune cells by conjugation to a TLR 9 agonist enhances antitumor immune responses. Nat. Biotechnol. 27, 925–933 (2009). [Abstract]

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