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The oxidative stress-sensing transcription factor Nrf2 has been studied by cancer researchers as a double-edged sword that can either promote or inhibit cancer. Previous findings have shown that Nrf2 can act as a tumor suppressor by detoxifying carcinogens. Paradoxically, when cancer cells express Nrf2, they are protected from oxidative stress and certain chemotherapies, thus explaining why some cancer cells constitutively activate Nrf2 as a tumor promoter. We recently found that the cytokine Interleukin (IL)-17D mediates the recruitment of natural killer (NK) cells to tumor sites, thereby leading to tumor rejection. Here, we show that Nrf2 induced IL-17D in primary tumors and tumor cell lines. Moreover, the known Nrf2-activator tBHQ induced Nrf2 and IL-17D simultaneously, without creating harmful oxidative stress. Applying a tBHQ-containing skin cream to established tumors led to NK cell-mediated tumor regression, and this depended on IL-17D and Nrf2. We propose that the use of tBHQ or other Nrf2 activators can intiate a tumor surveillance pathway involving IL-17D and NK cells, thus mediating cancer regression and bearing potential for cancer immune therapy.

Cells undergoing xenobiotic or oxidative stress activate the transcription factor Nrf2, which initiates an intrinsic “stress surveillance” pathway involving detoxifying enzymes. We recently found that the cytokine IL-17D effects a form of extrinsic stress surveillance by inducing antitumor immunity, but how IL-17D is regulated remains unknown. Here, we show that Nrf2 induced IL-17D directly in primary tumors as well as during viral infection in vivo. Expression of IL-17D in tumors and virally infected cells is essential for optimal protection of the host as il17d−/− mice experienced a higher incidence of tumors and exacerbated viral infections compared to WT animals. Moreover, activating Nrf2 to induce IL-17D in established tumors led to NK cell-dependent tumor regression. These data demonstrate that Nrf2 can initiate both intrinsic and extrinsic stress surveillance pathways and highlight the use of Nrf2 agonists as immune therapies for cancer and infection.