Inadequate oxygen supply, or hypoxia, is characteristic of the tumor microenvironment and correlates with poor prognosis and therapeutic resistance. Hypoxia leads to the activation of the hypoxia-inducible factor (HIF) signaling pathway and stabilization of the HIF-α subunit, driving tumor progression. The homologous alpha subunits, HIF-1α and HIF-2α, are responsible for mediating the transcription of a multitude of critical proteins that control proliferation, angiogenic signaling, metastasis, and other oncogenic factors, both differentially and sequentially regulating the hypoxic response. Post-translational modifications of HIF play a central role in its behavior as a mediator of transcription, as well as the temporal transition from HIF-1α to HIF-2α that occurs in response to chronic hypoxia. While it is evident that HIF-α is highly dynamic, HIF-2α remains vastly under-considered. HIF-2α can intensify the behaviors of the most aggressive tumors by adapting the cell to oxidative stress, thereby promoting metastasis, tissue remodeling, angiogenesis, and upregulating cancer stem cell factors. The structure, function, hypoxic response, spatiotemporal dynamics, and roles in the progression and persistence of cancer of this HIF-2α molecule and its EPAS1 gene are highlighted in this review, alongside a discussion of current therapeutics and future directions.

Synthetic receptors have emerged as powerful tools for precisely modulating cellular function. However, existing synthetic receptor platforms rely mainly on transcription-mediated reporting processes that are incompatible with the rapid and real-time dynamics of cellular signaling events. To address this limitation, we present SPN-FLUX (synthetic phosphorylation networks with fluorescence and luminescence expansion), a fully post-translational platform that integrates synthetic phosphorylation networks with split fluorescent or luminescent proteins, enabling rapid and tunable reporting of cellular processes. SPN-FLUX is responsive to extracellular stimuli within 1 h, providing a robust alternative to transcription-based approaches. Using mammalian cells as a model, we showcase SPN-FLUX's versatility by designing a membrane-bound receptor that activates upon ligand-induced dimerization, as well as a constitutively active intracellular biosensor. We further validate SPN-FLUX's biosensing capabilities by examining its responsiveness to hypoxic conditions, showcasing the ability to detect environmental changes dynamically. The modularity and programmability of SPN-FLUX establish it as a powerful platform for advancing synthetic biology and biosensing, with broad applications in both biomedical research and environmental monitoring.