Researchers at Johns Hopkins University and the University of Maryland School of Pharmacy report that novel small molecules inhibiting HIF-1 and HIF-2 can eradicate multiple tumor types in mice when combined with immunotherapy. The preclinical work, published in the Journal of Experimental Medicine, showed complete tumor elimination in models including breast, colorectal, melanoma, and prostate. The mechanistic rationale centers on hypoxia-inducible factors acting as transcriptional “master regulators” of tumor survival programs that can also blunt checkpoint blockade by altering immune cell function and tumor microenvironment signaling. For the field, the translational angle is the potential to overcome resistance to immune checkpoint therapies using a targeted hypoxia pathway approach. The next step for developers will be to translate the synergy into early clinical studies with clear biomarker strategies.