Hypoxia is a defining feature of the tumour microenvironment (TME) that drives aggressive tumour behaviour through coordinated adaptive responses. Hypoxia-inducible factors (HIFs), particularly HIF-1α, play a central role in orchestrating metabolic, immune and epigenetic reprogramming within tumours.

This review aims to elucidate the integrated roles of hypoxia in regulating angiogenesis, immune suppression, metabolic adaptation and epigenetic modifications, and to highlight their collective impact on tumour progression and therapeutic resistance.

A comprehensive review of current literature was conducted to examine the molecular and cellular mechanisms mediated by hypoxia and HIF signalling within the TME, with a focus on their interplay across angiogenic, immune, metabolic and epigenetic pathways.

HIF-1α promotes the expression of pro-angiogenic factors, including VEGF, ANGPT2 and CXCL12, leading to abnormal vascularisation and recruitment of immunosuppressive cells such as regulatory T cells and myeloid-derived suppressor cells. This disorganised vasculature exacerbates hypoxia, reinforcing a cycle of immune evasion and metabolic stress. Hypoxia also upregulates immune checkpoint molecules (e.g., PD-L1, PD-1), contributing to T-cell exhaustion and impaired dendritic cell function. Concurrently, metabolic reprogramming—characterised by increased glycolysis, lactate accumulation and extracellular acidification—suppresses cytotoxic T cell and NK cell activity. Epigenetic regulators, including histone demethylases and DNA methyltransferases, sustain these adaptations through persistent transcriptional changes, referred to as hypoxic memory.

Hypoxia acts as a central organising force within the TME, coordinating angiogenic, immune, metabolic and epigenetic processes to promote tumour progression. Targeting HIF-driven pathways represents a promising therapeutic strategy to overcome immune resistance, enhance drug delivery and improve the efficacy of combination treatments, including immunotherapy and metabolic interventions. This review underscores the importance of integrated approaches to disrupt hypoxia-mediated tumour adaptation.