Hypoxia and HIF Signalling in Tumour Microenvironment: Linking Immune Evasion, Metabolic Rewiring, and Epigenetic Regulation

Hypoxia is a key feature of the tumour microenvironment (TME) that promotes aggressive tumour behaviour through a coordinated adaptive response.Central to this process are hypoxiainducible factors (HIFs), especially HIF-1, which reprogram cellular metabolism, suppress immune surveillance, and alter the epigenetic landscape.HIF-1 increases the production of pro-angiogenic factors, such as VEGF, ANGPT2, and CXCL12, which facilitate abnormal vessel growth and attract immunosuppressive cells, such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs).This disorganized vasculature worsens hypoxia, creating a vicious cycle of immune evasion and metabolic stress.The immunosuppressive environment enhances immune checkpoint expression (e.g., PD-L1, PD-1), leading to T-cell exhaustion and reduced dendritic cell activity.Meanwhile, hypoxia-driven metabolic changes, including increased glycolysis, lactate accumulation, and extracellular acidification, directly impair the function of cytotoxic T cells and NK cells, further suppressing immune responses.Additionally, epigenetic regulators activated by HIFs, such as histone demethylases and DNA methyltransferases, help lock in these hypoxia-induced immune and metabolic states through persistent transcriptional programs, often called hypoxic memory.These interconnected mechanisms enable tumors to evade immune attack, support ongoing angiogenesis, and adapt metabolically within the TME.Importantly, hypoxia acts as a central organizing force rather than an isolated driver, coordinating angiogenic, metabolic, immune, and epigenetic processes to facilitate tumor progression.Understanding hypoxia's role in tumor biology has important clinical implications.Targeting HIF pathways can potentially restore tumour sensitivity to immune checkpoint therapies, counteract resistance, and improve drug delivery by normalizing blood vessels.Combining hypoxia-targeted treatments with immunotherapy or metabolic inhibitors offers promising prospects for enhancing treatment efficacy and patient outcomes in hypoxia-adapting cancers.This review explores the complex interactions among hypoxiainduced immune suppression, angiogenesis, metabolic adaptation, and epigenetic changes that influence tumor evolution.