Interaction of HIF-1a with various cell death pathways in tumor immune microenvironment (TIME)

Hypoxia-inducible factor-1 alpha (HIF-1α) is a key mediator of tumor adaptation to hypoxic stress. In addition to its canonical roles in angiogenesis and metabolic reprogramming, HIF-1α modulates multiple regulated cell death pathways, and shapes the tumor immune microenvironment (TIME). These interactions critically influence immune evasion and therapeutic resistance. This systematic review examines the crosstalk between HIF-1α and regulated cell death mechanisms within the TIME, with emphasis on their implications for immune modulation and cancer immunotherapy response.

A comprehensive search of PubMed, Scopus, and Web of Science (inception-July 2025) was conducted following PRISMA guidelines. Eligible studies included preclinical, in vivo, and clinical investigations exploring mechanistic links between HIF-1α, cell death pathways, and immune components. Data extraction and quality assessment were performed independently by two reviewers.

Seventy studies were included. Evidence indicates HIF-1α facilitates immune escape by promoting immunosuppressive TIME elements and inhibiting apoptosis, while contextually modulating pyroptosis and ferroptosis.

Understanding the crosstalk between HIF-1α, regulated cell death mechanisms, and the TIME provides critical insights into tumor adaptability and immune resistance. Targeting this axis may offer novel therapeutic opportunities to enhance the efficacy of cancer immunotherapies, particularly in hypoxic tumors with cold immune landscapes.