Hypoxia is a critical factor affecting tissue homeostasis that dramatically alters the tumor microenvironment (TME) through genetic, metabolic, and structural changes, promoting tumor survival and proliferation. Hypoxia-inducible factor-1α (HIF-1α) plays a central role in this process by regulating hundreds of genes involved in the processes of tumorigenesis, angiogenesis, metabolic reprogramming, and immune evasion. This review provides a comprehensive examination of the role of HIF-1α in hypoxia and how hypoxia weakens intercellular junctions—including gap junctions, adherens junctions, tight junctions, and desmosomes. The disruption of gap junctions decreases intercellular communication, which alters signal transduction cascades and tumor suppressive properties. Adherens junctions are comprised of proteins that characterize the tissues and link cells to the actin cytoskeleton, whereby their disruption promotes the epithelial-to-mesenchymal transition (EMT). Under hypoxic conditions, the tight junction proteins are dysregulated, altering paracellular transport and cell polarity. In addition, desmosomes provide linkage to intermediate filaments, and hypoxia compromises tissue integrity. Collectively, the influence of hypoxia on cellular junctions promotes tumorigenesis through reducing cell communication, cytoskeletal interactions, and altering signaling pathways. Activation of matrix metalloproteinases (MMPs) further degrades the extracellular matrix and enhances tumor invasion and metastasis. This process also involves hypoxia-induced angiogenesis, regulated by HIF-1α. A comprehensive understanding of the mechanisms of hypoxia-driven tumor adaptation is essential for developing effective therapeutic strategies. Furthermore, this review examines current treatments aimed at targeting HIF-1α and explores future directions to enhance treatment efficacy and improve patient outcomes.

Hypoxia is a critical factor driving cellular adaptation, reshaping the tumor microenvironment (TME) through genetic, metabolic, and structural changes that promote tumor survival and proliferation. Hypoxia-inducible factor-1α (HIF-1a) plays a central role in this process by regulating angiogenesis, metabolic reprogramming, and immune evasion through numerous pathways, ultimately enabling tumor cells to survive, invade, and develop therapy resistance. This article examines how hypoxia weakens intercellular junctions—including gap junctions, adherens junctions, tight junctions, and desmosomes—thereby disrupting intercellular contacts and communication to promote invasion. Additionally, it explores the activation of matrix metalloproteinases (MMPs) under hypoxia, which further degrades the extracellular matrix and enhances the invasion. Hypoxia-induced metabolic and genetic changes induce the epithelial-to-mesenchymal transition (EMT), facilitating tumor cell invasion and metastasis. This process also involves hypoxia-induced angiogenesis, regulated by HIF-1a. A comprehensive understanding of the mechanisms of hypoxia-driven tumor adaptation is essential for developing effective therapeutic strategies. This article explores the molecular pathways that regulate angiogenesis, metabolic reprogramming, cell migration and immune evasion, illustrating how changes in the tumor microenvironment ultimately lead to metastasis. Given the role of hypoxia in treatment resistance, targeting HIF-1α and its downstream effectors could potentially enhance treatment efficacy and improve patient outcomes.

Pancreatic adenocarcinoma remains a highly lethal malignancy with limited effective treatment options, largely due to late-stage detection and rapid progression to metastatic disease. Therapeutic strategies capable of targeting both pre-metastatic and metastatic tumors are critically needed. In this study, we evaluated a combination therapy consisting of non-thermal plasma (NTP), a generator of reactive oxygen and nitrogen species, and the hypoxia-activated prodrug tirapazamine (TPZ). We further investigated whether sulforaphane (SF), a bioactive phytochemical, could further enhance therapeutic efficacy. NTP and TPZ produced strong cytotoxic effects as single agents and demonstrated additive to synergistic activity when combined, reducing viability by 87% in pre-metastatic BxPC-3 cells and achieving near-complete elimination of metastatic AsPC-1 cells. The addition of sulforaphane (10 µM) further enhanced cytotoxicity across all treatment conditions, with Bliss independence analysis indicating additive to synergistic interactions depending on cell line and treatment combination. Sulforaphane-mediated enhancement occurred without restoration of connexin 43 expression or coordinated reversal of epithelial-to-mesenchymal transition markers, and treatments did not induce N-cadherin upregulation or suggest acquisition of invasive characteristics. Together, these findings support NTP + TPZ as a potent combinatorial strategy for pancreatic adenocarcinoma and identify sulforaphane as an effective adjunct that enhances cytotoxic efficacy through mechanisms that remain to be fully elucidated.