Interplay between ER stress and DNA repair pathways in solid tumors under hypoxia

Solid tumors often develop a hypoxic microenvironment that triggers adaptive cellular responses, promoting tumor progression, aggressiveness, and therapeutic resistance. Hypoxia activates HIF1α, a key regulator that modulates the expression of genes involved in metabolic reprogramming and angiogenesis. Hypoxia disrupts protein homeostasis by compromising endoplasmic reticulum (ER) function, resulting in ER stress (ERS) and subsequent activation of the ER stress response (ERSR), collectively known as the unfolded protein response (UPR). Hypoxic stress also induces DNA damage and genomic instability, driven by replication stress and dysregulated DNA damage repair (DDR) pathways. In this review, we examine the current understanding of the mechanisms by which UPR sensors interface with DDR components to influence cancer cell fate under hypoxic conditions. Elucidating the mechanistic crosstalk among these hypoxia-responsive stress pathways will provide a better understanding of tumor evolution and metastasis. Furthermore, it highlights the cellular vulnerabilities emerging from this interplay that may be leveraged for therapeutic interventions.