Hypoxic microenvironment in cancer: molecular mechanisms and therapeutic interventions

Abstract

Having a hypoxic microenvironment is a common and salient feature of most solid tumors. Hypoxia has a profound effect on the biological behavior and malignant phenotype of cancer cells, mediates the effects of cancer chemotherapy, radiotherapy, and immunotherapy through complex mechanisms, and is closely associated with poor prognosis in various cancer patients. Accumulating studies have demonstrated that through normalization of the tumor vasculature, nanoparticle carriers and biocarriers can effectively increase the oxygen concentration in the tumor microenvironment, improve drug delivery and the efficacy of radiotherapy. They also increase infiltration of innate and adaptive anti-tumor immune cells to enhance the efficacy of immunotherapy. Furthermore, drugs targeting key genes associated with hypoxia, including hypoxia tracers, hypoxia-activated prodrugs, and drugs targeting hypoxia-inducible factors and downstream targets, can be used for visualization and quantitative analysis of tumor hypoxia and antitumor activity. However, the relationship between hypoxia and cancer is an area of research that requires further exploration. Here, we investigated the potential factors in the development of hypoxia in cancer, changes in signaling pathways that occur in cancer cells to adapt to hypoxic environments, the mechanisms of hypoxia-induced cancer immune tolerance, chemotherapeutic tolerance, and enhanced radiation tolerance, as well as the insights and applications of hypoxia in cancer therapy.

Tumor microenvironment-responsive degradable silica nanoparticles: design principles and precision theranostic applications

“…Consequently, tumor tissues often develop abnormal vascular networks, causing stasis and reduced blood flow, which in turn leads to tumor hypoxia. [118][119][120][121] Under conditions of inadequate oxygen supply, the effectiveness of tumor treatments, including CMT, RT, and phototherapy, is limited, resulting in severe consequences such as tumor recurrence and high mortality rates. 118,122,123 Notably, quinones, nitroaromatics, azobenzene derivatives, and other functional groups serve as examples of hypoxia-responsive moieties.…”

Extracellular Matrix Regulation in Physiology and in Brain Disease

“…HIF-1 also targets genes involved in ECM remodeling, including collagen synthesis and some metalloproteinases, suggesting that hypoxia could contribute to ECM remodeling [ 78 ]. Studies that examine the role of hypoxia and HIF-1 in promoting metastasis in cancer are examples of how HIF-1 activation can regulate the expression of ECM components including MMPs to alter ECM physiology [ 79 ]. Even a single hypoxic event can induce long-lasting changes in the ECM, as demonstrated in perinatal rats which exhibited altered PNN composition in the cingulate cortex that persisted into adulthood from exposure to a single hypoxic event [ 80 ].…”

Cascade strategy for glucose oxidase-based synergistic cancer therapy using nanomaterials

“…252 Under hypoxic conditions, HIF-1 is attached to hypoxia response elements (HREs) in the promoters of hypoxia-activated genes to initiate transcription. 253 Suicide gene therapy is one prospective therapeutic technique in which therapeutic genes are transfected into cellular DNA. 254 When expressed, the gene product kills the cell directly, initiates a robust immune response, or activates the toxicity of a non-toxic prodrug.…”