Potential Pathophysiological Pathways in the Complex Relationships between OSA and Cancer

Obstructive sleep apnea (OSA) exhibits phenotypic heterogeneity, but two consequences—intermittent hypoxemia (IH) and sleep fragmentation (SF)—drive much of its systemic impact on cardiovascular, metabolic, and neurocognitive outcomes. Emerging evidence indicates that IH and SF can activate biological mechanisms linking OSA to higher prevalence, incidence, and aggressiveness of certain cancers. Early work implicated IH-driven upregulation of HIF-1α and downstream VEGF, promoting tumor neovascularization and metastasis. Since then, additional mechanisms involving genetic, molecular, cellular, and microbiome determinants have been identified. The diversity of these pathways and their variable effects on tumor cell metabolism and microenvironments likely underlie heterogeneous associations between OSA and specific cancer histologies and sites. This review summarizes current pathophysiological mechanisms that may explain OSA–cancer links and highlights future research challenges.

The review synthesizes epidemiologic and clinical observations suggesting increased cancer incidence or aggressiveness in OSA, with heterogeneity by tumor type (e.g., melanoma and some breast and lung cancers vs. prostate or liver). Mechanistic studies in patients, animal models, and in vitro systems demonstrate IH-induced oxidative stress and inflammation, NF-κB activation, and altered immune surveillance (macrophage polarization shifts, reduced NK and γδ T-cell cytotoxicity, PD-1/PD-L1 upregulation, dendritic cell depletion). Tumor biology studies show IH fosters EMT/CSC phenotypes via TGF-β and PSPC1, and modulates tumor–stroma interactions, including COX-2/PGE2 pathways. Biomarker investigations report associations of tumor HIF-1α (but inconsistent VEGF) with melanoma aggressiveness, higher VCAM-1 in OSA with melanoma, and elevated soluble PD-L1 correlating with melanoma aggressiveness and sentinel node status. Genetic literature indicates pleiotropic mechanisms: HIF1A expression is induced by CIH; genome-wide signals (e.g., NRG1) link hypoxic response pathways to OSA severity and cancer; OSA-associated loci include KDM2B and BDNF with roles in glucose metabolism and tumor biology. Multiple studies describe differential miRNA signatures (e.g., miR-320b downregulation under IH promoting tumorigenesis) and exosome-mediated intercellular communication altering cancer cell proliferation, migration, and invasion. Microbiome research shows IH/SF-induced gut dysbiosis recapitulates OSA morbidities and may influence oncogenesis and therapy responses, suggesting bidirectional links among OSA, microbiota, and cancer.

- IH and SF are central OSA features activating cancer-relevant pathways. HIF-1α is a key mediator linking hypoxemia to angiogenesis, metabolism, and immune modulation. - Immune dysfunction: IH triggers oxidative stress and NF-κB signaling, elevating IL-6, IL-1β and activating the NLRP3 inflammasome. Macrophage polarization shifts toward pro-inflammatory M1 in non-malignant tissues, while tumor sites in IH-exposed mice often show higher M2 subsets. Dendritic cells are reduced in OSA; NK and γδ T-cell cytotoxicity is impaired; iNKT cells are decreased. - T-cell surveillance: PD-1 is upregulated on CD4+/CD8+ T cells, and PD-L1 on monocytes in OSA; higher circulating sPD-L1 correlates with cutaneous melanoma aggressiveness and improves sentinel lymph node metastasis prediction by 27.3% when added to classic risk factors. - EMT/CSC programs: IH promotes EMT-TFs (TWIST, SNAIL, SLUG) and CSC regulators (OCT4, SOX2, NANOG) via TGF-β/PSPC1; OSA severity associates with higher serum PSPC1 in melanoma. - Biomarkers: Tumor HIF-1α expression correlates with melanoma aggressiveness and OSA hypoxemia indices; VEGF shows inconsistent associations with tumor malignancy in OSA. VCAM-1 is elevated in patients with OSA and melanoma. TGF-β1 correlates with melanoma aggressiveness particularly in non-obese patients; TNF-α levels rise with OSA severity. IH induces COX-2/PGE2; cannabinoid receptor upregulation under chronic IH promotes breast cancer cell proliferation and migration. Endostatin exhibits enhanced anti-tumor effects under IH in mice. Endothelin-1 receptor blockade prevents IH-induced tumor development in preclinical models. - Genetics/epigenetics: CIH induces HIF1A and downstream oncogenic/metabolic genes (e.g., ATAD2, HK2). GWAS identify hypoxia pathway and metabolism genes associated with OSA (e.g., NRG1, KDM2B, BDNF), many implicated in cancers, supporting pleiotropy. Multiple miRNAs are differentially expressed in IH and OSA; miR-320b downregulation under IH promotes lung cancer tumorigenesis via CDT1/USP37; diagnostic miRNA panels for OSA are feasible. - Exosomes: OSA/IH alter exosomal miRNA cargo; exosomes from OSA or obesity hypoventilation plasma enhance tumor proliferation, migration, and invasion in vitro. Hypoxia-sensitive melanoma cells showed 46 differentially expressed exosomal miRNAs under IH vs. 8 in hypoxia-resistant cells, implicating Ras/MAPK/ErbB/AMPK/cAMP pathways. - Microbiota: IH/SF induce gut dysbiosis, inflammation, metabolic dysfunction, and may influence cancer risk and therapy response; probiotic/prebiotic interventions show promise in ameliorating OSA-related morbidities. - Heterogeneity: Tumor type and microenvironment determine OSA impact; melanoma and some breast/lung cancers appear more responsive to IH effects than prostate or liver cancer lines in preclinical/clinical observations.

The compiled evidence supports a biologically plausible, yet heterogeneous, association between OSA and cancer, primarily mediated by intermittent hypoxia and, to a lesser extent, sleep fragmentation. IH-driven HIF-1α activation intersects with inflammatory and immune checkpoint pathways, altering innate and adaptive immunity, fostering EMT/CSC traits, and remodeling the tumor microenvironment. Biomarkers such as HIF-1α, sPD-L1, VCAM-1, TGF-β1, and COX-2/PGE2 components may stratify risk or aggressiveness in specific cancers (notably melanoma), while VEGF shows inconsistent utility. Genetic pleiotropy and epigenetic regulation (miRNAs) likely contribute to inter-individual variability. Exosomes and gut microbiota emerge as key mediators linking OSA to tumor biology and potentially to therapy responses. These findings address why OSA may worsen outcomes in select cancers and suggest opportunities for biomarker-guided risk assessment and targeted interventions (e.g., COX-2 or endothelin receptor blockade, modulation of PD-1/PD-L1 axes). However, clinical translation remains preliminary, and effects of OSA treatments (e.g., CPAP) on cancer endpoints are not established.

The relationship between OSA and cancer is complex and heterogeneous, influenced by tumor histology, microenvironment, and patient factors (age, sex, comorbidities, treatments). Multiple converging mechanisms—HIF-1α signaling, immune dysregulation with PD-1/PD-L1 upregulation, EMT/CSC programs via TGF-β/PSPC1, exosome-mediated communication, genetic pleiotropy, and microbiota alterations—likely underlie increased cancer risk or aggressiveness in subsets of patients with OSA. Future work should (1) delineate which tumor types are most affected by OSA and dominant pathways for each; (2) validate and standardize biomarkers predicting cancer risk/aggressiveness in OSA; (3) determine whether effective OSA therapies (CPAP or alternatives) reduce cancer incidence or progression; (4) define which cancer patients warrant OSA screening; (5) expand genetic/epigenetic and microbiome research to identify novel diagnostics and therapeutic targets.

- Narrative review without a specified systematic search strategy; potential selection bias in included evidence. - Heterogeneity across studies (populations, OSA definitions/severity metrics, tumor types, endpoints) limits generalizability and causal inference. - Biomarker associations (e.g., VEGF) are inconsistent; many findings are preliminary and require replication and standardization. - Predominance of preclinical and translational data (animal models, in vitro, ex vivo exosomes); limited prospective clinical trials linking OSA treatment to cancer outcomes. - Tumor-type specificity and microenvironmental diversity complicate extrapolation; differential responses to IH across cell lines and cancers may not reflect clinical behavior across all patients. - Exosome and microbiome mechanisms remain early-stage with uncertain clinical applications.