From mild to severe hypoxia: How HIF-1α conducts the “survival symphony” of tumor cells?

Background

In various physiological and pathological contexts—including cancer, tissue ischemia, and stem cell homeostasis—cells are often exposed to a graded hypoxic continuum ranging from mild to moderate to severe oxygen deprivation. It is now widely accepted that HIF-1 serves as the "conductor" of hypoxic adaptation, orchestrating key cellular responses such as metabolic reprogramming, immune modulation, survival strategies, and angiogenesis by activating approximately 60 to 100 core target genes. However, how cells sense the severity of hypoxia and precisely regulate HIF-1 activity to fine-tune downstream gene expression and functional outputs remains incompletely understood. In particular, the roles of upstream regulators—such as prolyl hydroxylases (PHDs) and factor inhibiting HIF (FIH)—in mediating this nuanced control warrant further investigation. 

Research Progress

To elucidate the molecular mechanisms underlying cellular response to graded hypoxia, Wei Wang's team at Nanjing University, developed a quantitative regulatory network model of HIF-1α. By integrating dynamic simulations, bifurcation analysis, mechanistic prediction, and functional validation, the study systematically revealed that HIF-1α activation is a progressive process. This activation is primarily governed by the sequential inactivation of two classes of hydroxylases—prolyl hydroxylases (PHDs) and factor inhibiting HIF (FIH)—which orchestrate tiered cellular adaptive responses.

Specifically, under mild hypoxia (~2% O₂), PHDs are first inactivated, leading to the stabilization of HIF-1α and exposure of its N-terminal transactivation domain (N-TAD), conferring partial transcriptional activity and inducing glycolytic enhancement and immune suppression. As oxygen tension further decreases to moderate hypoxia (~0.7% O₂), FIH becomes inactivated, resulting in the exposure of both N-TAD and C-terminal TAD (C-TAD), and thus the fully activated HIF-1α robustly induces angiogenic responses. Under severe hypoxia (<0.5% O₂), the fully activated HIF-1α accumulates to high levels, leading to lactate buildup, acidosis, and eventually programmed necrosis.

Thus, HIF-1α adopts distinct transcriptional activation configurations under different oxygen levels, driving stage-specific gene expression programs that coordinately regulate diverse cellular outcomes (Figure 1). Further investigations identified miR-182 as a “sliding regulator” that dynamically fine-tunes HIF-1α functional output across different activation phases. Notably, a coupled positive and negative feedback loop comprising HIF-1α, PHD-2, FIH, and miR-182 endows the cell with high sensitivity and precision in oxygen sensing, thereby establishing a framework for cellular adaptation to hypoxia involving in the progress from oxygen sensing to achieving functional compatibility.

Future Perspectives

This model clearly delineates how oxygen gradients induce differential inactivation of hydroxylases and sequential activation of associated functional modules, thereby providing a theoretical foundation for identifying “precision targets” within the HIF signaling axis. The elucidation of this tiered hypoxic response mechanism holds promise for the development of more refined therapeutic strategies—such as small-molecule inhibitors targeting glycolysis or angiogenesis, selective elimination of therapy-resistant cells residing in different hypoxic regions.

Currently, various oxygen-sensing technologies have been developed to assess oxygen distribution even in deep tissues, including the bone marrow, making the construction of spatial oxygenation maps increasingly feasible. Systematic characterization of tumor responses to graded and cyclic hypoxia—as well as the corresponding adaptive strategies employed—may offer more targeted approaches to counteract hypoxia-driven tumor progression and poor clinical outcomes. Notably, specific hypoxia-induced responses (such as angiogenesis or immune evasion) may be differentially activated across spatially distinct hypoxic zones, potentially leading to significant variations in drug efficacy within the tumor microenvironment.

Therefore, incorporating hypoxia partitioning into the design of combination therapies—and accounting for the spatial coupling between drug transport and hypoxia adaptation—could help overcome the limitations of monotherapies, such as insufficient efficacy or compensatory resistance mechanisms, ultimately enhancing the overall anti-tumor effects.

Sources: https://spj.science.org/doi/10.34133/research.0651