A form of cell communication called hedgehog signaling is vital for embryonic development in mammals. But aberrantly activated hedgehog signaling in multiple cancer types including breast cancer promotes tumor invasion, its spread to other organs and multi-drug resistance.

This signaling by the tumor microenvironment suggests that use of existing, clinically approved hedgehog-signaling inhibitors may diminish the tumor-promoting properties of tumor-associated M2 macrophages within the tumor microenvironment. Elevated infiltration of immunosuppressive, alternatively polarized M2 macrophages is associated with poor prognosis in cancer patients.

The allure of targeting hedgehog signaling stems from the availability of several U.S. Food and Drug Administration-approved inhibitors already in use in the clinic, making it applicable to different tumor types. Our work supports the possibility that hedgehog blockade is multi-dimensional in its effect on recalibrating the metabolism, and consequently, the functions of immunosuppressive macrophages.

Thus, inhibition of hedgehog signaling could present with the dual benefit of directly targeting tumor cells and re-configuring the tumor immune microenvironment to an immune-activated state. M1 and M2 macrophages have distinct metabolic circuitries that contribute to their survival and different functions in the immune response. M1 macrophages have a metabolism that creates energy through glycolysis, which is sufficient for their tumor-eradicating functions, while M2 macrophages use oxidative phosphorylation, which is a much more efficient way to produce the energy needed for their tumor-promoting functions.

Regards

John
EditorialAssistant
Immunogenetics Open Access