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Liver cancer: overcoming treatment resistance Targeting hypoxia-inducible factors (HIFs), regulatory proteins induced by low oxygen levels, could increase the effectiveness of sorafenib, the only systemic therapy approved for advanced liver cancer. Long-term treatment with sorafenib starves tumors of oxygen, which can lead to the proliferation of cancer cells that are able to survive low oxygen levels. HIFs regulate genes involved in this adaptation and HIF levels are increased in sorafenib-resistant cells. José Mauriz at the University of León, Spain, and colleagues review recent studies on the effects of HIF inhibition on sorafenib efficacy. They conclude that HIF-1α and HIF-2α are predictive markers of sorafenib resistance and that using inhibitors of both these factors as an add-on therapy could improve patient survival. This strategy may be applicable to other types of cancer in which reduced oxygen conditions lead to drug resistance.