Obstructive sleep apnea (OSA) is characterized by intermittent hypoxemia (IH) and sleep fragmentation (SF), both of which have systemic impacts on an individual's cardiovascular, metabolic, and neurocognitive health. Recent research suggests that IH and SF may also contribute to the increased prevalence, incidence, and aggressiveness of certain cancers. Early research focused on the hypoxia-inducible factor (HIF-1α) pathway and its role in increasing vascular endothelial growth factor (VEGF), leading to tumor neovascularization and metastasis. However, the relationship between OSA and cancer is complex and heterogeneous, influenced by various factors including age, gender, comorbidities (particularly obesity), treatments, and the specific histological type and location of the cancer. This review explores the diverse pathophysiological mechanisms linking OSA and cancer, encompassing genetic, molecular, cellular, and microbiological determinants, and highlights the need for further research to fully understand this association and develop effective interventions.

The literature review extensively examines existing research on the relationship between OSA and cancer. It covers epidemiological studies showing correlations between OSA and increased cancer incidence or severity, highlighting the heterogeneity of these findings across different cancer types. The review discusses previous research on the role of HIF-1α in mediating the effects of intermittent hypoxia on tumor growth and angiogenesis. It also synthesizes evidence on the involvement of other pathophysiological pathways, such as immune cell dysfunction, biomarker alterations (VEGF, TGF-β, TNF-α, etc.), exosomes, genetic factors (HIF1A, NRG1, KDM2B, BDNF, microRNAs), and microbiome changes. The review analyzes various studies using both clinical data from OSA patients and murine models of OSA, comparing the observed responses in different tumor cell lines.

This is a review article; therefore, it does not involve original data collection or experimentation. The methodology centers on a comprehensive review of published literature on the pathophysiological links between OSA and cancer. The authors systematically searched databases for relevant studies, focusing on epidemiological findings, mechanistic studies in both human subjects and animal models, and investigations into the molecular and cellular pathways potentially involved. The search encompassed various types of studies, including epidemiological studies assessing the association between OSA and cancer risk, experimental studies elucidating the mechanisms by which OSA might influence cancer development and progression, and clinical studies investigating the impact of OSA on cancer prognosis and treatment outcomes. The included studies were critically appraised for their methodological quality, and the findings were synthesized to provide a comprehensive overview of the current state of knowledge. The information gathered was organized thematically, examining the roles of cell dysfunction, specific biomarkers, genetic factors, exosomes, and the microbiota in the relationship between OSA and cancer. The authors used several databases such as DisGeNET 7.0 to identify genes implicated in OSA and cancer. The findings from this literature review are then presented and discussed to highlight the complexity of the relationship between OSA and cancer and propose future areas of research.

The review highlights the heterogeneity of the OSA-cancer relationship, emphasizing that the association varies significantly across different cancer types. Intermittent hypoxia, a hallmark of OSA, plays a central role through the HIF-1α pathway, influencing various cellular and molecular processes. Key findings include: * **Immune Dysfunction:** OSA-related IH and SF disrupt immune function by altering macrophage polarization (increased M1, decreased M2), reducing NK cell and γδ T-cell cytotoxic activity, and impairing T-cell function (increased PD-1/PD-L1 expression). This immune dysregulation fosters a pro-tumorigenic environment. * **Biomarker Alterations:** Several biomarkers are implicated, including HIF-1α (linked to melanoma aggressiveness), VEGF (inconsistent relationship with OSA severity and tumor malignancy), VCAM-1 (increased in OSA patients with melanoma), sPD-L1 (correlated with melanoma aggressiveness), TGF-β1 (associated with melanoma aggressiveness, particularly in non-obese patients), PSPC1 (upregulated by IH), TNF-α (increased in OSA, potential link to tumor progression), COX-2/PGE2 (upregulated by hypoxia), cannabinoid receptors (linked to breast cancer proliferation and migration), endostatin (anti-tumor effect enhanced by IH), and endothelin-1 (cancer promotion under IH). * **Genetic Factors:** Genetic variations in HIF1A (encoding the HIF-1α subunit), NRG1 (promotes HIF-1α accumulation), KDM2B (involved in glucose metabolism and HIF-1α regulation), and BDNF (modulates insulin sensitivity) may influence both OSA and cancer susceptibility. MicroRNA alterations, both circulating and exosomal, are also linked to cancer proliferation and response to hypoxia. * **Exosomes:** Exosomes released by tumor cells and other cells in the tumor microenvironment act as messengers, transferring molecules (like miRNAs) that influence tumor growth, metastasis, and response to hypoxia. OSA-related IH alters the exosomal miRNA cargo, potentially contributing to cancer progression. * **Microbiota:** Alterations in the gut microbiome (dysbiosis) induced by OSA may contribute to cancer development through chronic inflammation and the production of harmful metabolites. Research in this area is still emerging, but preliminary findings suggest potential benefits from pre- and probiotic interventions.

The findings of this review reinforce the plausibility of a true association between OSA and cancer, although further investigation is needed to fully elucidate this complex relationship. The heterogeneity in the observed clinical associations likely stems from the interplay of multiple pathophysiological pathways, the varying responses of different tumor cell lines to IH, and the influence of genetic and environmental factors. The role of IH as a key driver of cellular and molecular changes underlying the link between OSA and cancer is emphasized. The study of biomarkers, particularly those associated with immune function and tumor progression, holds potential for improving risk stratification and developing personalized therapeutic strategies. Furthermore, the emerging role of exosomes and the gut microbiome in mediating the effects of OSA on cancer warrants further research, potentially uncovering novel therapeutic targets.

This review summarizes the multiple, interconnected pathophysiological pathways linking OSA and cancer, highlighting the significant heterogeneity of this association across different cancer types. While the evidence points towards a real link, particularly via the impact of intermittent hypoxia, more research is needed to identify the specific tumor types most affected, the key pathways involved in each case, the role of OSA treatment in modifying cancer risk or progression, and the optimal screening strategies for OSA in individuals with cancer or a high cancer risk. Further investigation into the roles of exosomes, the microbiome, and the interaction of genetic and environmental factors is crucial for a complete understanding.

As a review article, this study is limited by the existing literature. The heterogeneity of previous studies regarding OSA and cancer makes it difficult to draw definitive conclusions about the strength and specificity of this association. Further large-scale, well-designed studies are needed to address the limitations of existing data, including the specific cancer types most significantly affected, optimal marker identification for association studies, and the impact of OSA treatment on cancer outcomes.