The TME is a dynamic environment made up of various cellular players, including fibroblasts, immune cells, inflammatory cells, epithelial cells, endothelial cells, mesenchymal cells, adipocytes, and extracellular matrix (ECM) (Ping et al., 2021). The substantial reciprocal communications between altered tumor cells and the dynamic TME establish pathways and signalling networks that drive tumorigenesis and cancer progression (Yuan et al., 2022). Growing evidence has shown that exposure to CIH fosters the development of stable genotypic and phenotypic traits, which can significantly enhance tumor advancement (Verduzco et al., 2015) and modulate the communication between tumor cells and stromal cells via the COX-2/PGE2 signaling pathway (Picado and Roca-Ferrer, 2020). Meanwhile, CIH may affect cytokine levels in the TME, such as tumor necrosis factor-α (TNF-α), interleukin-8 (IL-8), and interleukin-6 (IL-6), through the activation of NF-κB (Li et al., 2011). Ma et al. observed that CIH exposure lowers interleukin-17 (IL-17) level while boosting the levels of interleukin-10 (IL-10) and TNF-α within solid tumors, which facilitates tumor immune evasion within the TME, thus fueling tumor progression and malignancy (Ma et al., 2021). In summary, CIH may enhance solid tumor progression and metastasis by modulating the tumor’s inflammatory microenvironment and immune response.

Research also indicates that obesity is closely associated with multiple types of cancer, particularly lung cancer. The biological mechanisms linking obesity to lung cancer risk are multifaceted, potentially involving complex interactions between adipose tissue, systemic chronic inflammation, and insulin resistance. Firstly, adipose tissue leads to the secretion of pro-inflammatory cytokines and adipokines, such as TNF-α, IL-6, and leptin, thereby creating a TME conducive to cancer progression and metastasis (Liu X. et al., 2023; Lee et al., 2015). Then, excess weight leads to an expansion of adipose tissue, resulting in hypoxia and oxidative stress (Sergeeva et al., 2023). Reactive oxygen species (ROS) brought on by CIH directly damage DNA, inducing gene mutations, and further activate inflammatory pathways, such as the promotion of TNF-α and IL-6 release, forming a synergistic effect with obesity-related chronic inflammation (Ekin et al., 2021; Lamabadusuriya et al., 2025). Finally, Liu J. et al. found that insulin resistance is significantly positively correlated with the risk of lung cancer (Liu et al., 2024). The underlying mechanism may involve abnormal expression of proteins such as the insulin-like growth factor 1 receptor (IGF-1R) and the insulin receptor substrate 2 (IRS2), and the abnormal activation of these molecules may be implicated in the growth regulation of lung cancer cells (Shahid et al., 2024; Piper et al., 2019). Overall, targeting adipocytes, cytokines, and their signaling pathways presents a promising strategy for cancer treatment.

Cancer-associated fibroblasts (CAFs) are among the most important players in the TME and are activated fibroblasts exhibiting remarkable adaptability and heterogeneity in the TME, with diverse functions in tumor initiation, progression, invasion, and metastasis that have been extensively studied (Ping et al., 2021; Biffi and Tuveson, 2021). However, the lack of well-characterised markers and a uniform terminology to describe different phenotypes is a major obstacle to understanding the biological characteristics of CAFs. Recent research has specifically highlighted their role in identifying distinct tumor cell features and microenvironment compartments that displayed remarkable heterogeneity and dynamic changes in response to treatment, by using technological advances, such as single-cell RNA-sequencing (scRNA-seq) (Yan et al., 2025; Cords et al., 2024). Interestingly, recent studies indicate that CIH accelerates the advancement of lung cancer by boosting the mobility of lung cancer cells through upregulating transforming growth factor β (TGF-β) signaling, thereby increasing the activation and proportion of lung CAFs (Cui et al., 2023). Thus, we believe that CAFs would be targeted more precisely following the advances in cRNA-seq and provide therapeutic benefits for OSA-associated lung cancer patients.

It has been reported that hypoxia triggers angiogenesis and metastasis. Hypoxic conditions stabilize hypoxia-inducible factor-1 (HIF-1), thereby promoting angiogenesis and metabolic reorganization (Fu et al., 2021). Furthermore, hypoxia triggers a substantial buildup of lactate, creating an acidic setting. Within the TME, this low pH compromises the effectiveness of cytotoxic CD8⁺ T cells and natural killer (NK) cells, while simultaneously amplifying the immunosuppressive activity of CAFs. Meanwhile, these conditions can also promote cancer cell proliferation (Boedtkjer and Pedersen, 2020). This may be a potential mechanism by which OSA leads to lung cancer progression.

Exosomes are vesicular mediators equipped with a lipid bilayer structure that carry biomolecules such as signal transduction proteins, metabolites, and microRNAs (miRNAs) to transmit signals between cells. Serving as key regulatory carriers in the progression of OSA-associated lung cancer, they modulate tumor cell proliferation, drug resistance, and immune responses within the TME (Jeppesen et al., 2019). CIH, a core pathophysiological feature of OSA, markedly promotes exosome secretion from tumor cells. These exosomes not only enhance the malignant phenotype of tumor cells and disrupt endothelial barrier integrity but also exert pro-tumor effects that are reversible via CPAP treatment (Almendros et al., 2016; Khalyfa et al., 2018a; Khalyfa et al., 2018b). Additionally, hypoxia-induced exosomes have been shown to drive the progression of lung cancer, as well as breast cancer, prostate cancer, and other malignancies (King et al., 2012; Ramteke et al., 2015; Kucharzewska et al., 2013), by regulating angiogenesis, stemness, and other processes (Ramteke et al., 2015; Kucharzewska et al., 2013; Ren et al., 2024).

miRNAs encapsulated in exosomes are core molecules regulating lung cancer, among which miR-210 and miR-106a-5p have the most well-defined mechanisms. miR-210 is upregulated by hypoxia-inducible factor-1α (HIF-1α) under CIH conditions, and synergistically regulates key processes such as angiogenesis, epithelial-to-mesenchymal transition (EMT), and therapy resistance by targeting downstream molecules including PTPN1 (enhancing immune escape), SDHD (inducing mitochondrial metabolic reprogramming), and E2F3 (promoting lung adenocarcinoma development) (Goyal et al., 2025; Zhang et al., 2024). miR-106a-5p induces M2 polarization of macrophages by inhibiting PTEN or activating the STAT3 signaling pathway, thereby enhancing the proliferation and invasion abilities of non-small cell lung cancer (NSCLC) (Ren et al., 2024).

Other differentially expressed miRNAs mainly function in a synergistic network: 11 differentially expressed miRNAs, such as mmu-miR-671-5p, mmu-miR-609, mmu-miR-5113, and others, identified in exosomes from CIH-exposed mice are primarily involved in post-transcriptional modification, protein synthesis, cell morphology, cellular compromise, and other functions (Almendros et al., 2016). Additionally, hypoxia can also inhibit miR-27a expression via the NRF2 pathway, relieving its inhibition on BUB1 and facilitating lung cancer cell proliferation and EMT (Liu C. et al., 2023). Moreover, exosomes derived from NSCLC patients with OSA can directly promote PD-L1 expression in macrophages, enhancing immunosuppressive effects (Liu Y. et al., 2022).

Given the excellent stability and detectability of exosomal miRNAs in body fluids, these molecules not only provide critical insights into the interaction mechanisms between OSA and lung cancer but also hold promise as non-invasive biomarkers for early disease diagnosis and therapeutic monitoring, offering new directions for clinical precision intervention.

Tumor-associated macrophages (TAMs) are a kind of innate immune cell in cancers. M1-M2 polarization axis is associated with cancer progression; M1 phenotype macrophages are tumor-resistant and can enhance anti-tumor inflammatory reactions, while the M2 phenotype has tumor-promoting capabilities involving angiogenesis, immunosuppression, and neovascularization, as well as stromal activation and remodeling (Malfitano et al., 2020). Both adipose tissues (AT) around the tumor and bone marrow (BM)-derived progenitor cells represent potential macrophage sources (Wagner et al., 2012). In addition, the interactions between various cells could result in macrophage function changes in the TME (Wang et al., 2022).

In the mouse model of lung cancer, Almendros et al. revealed that CIH could regulate the interaction between tumor cells and AT, promote the transformation into adipose tissue macrophages (ATMs), and increase BM-derived ATMs. Furthermore, the M2/M1 ratio increased in IH mice, showing that the TAMs may experience a polarity shift toward an activated M2 macrophage phenotype. Thus, macrophages may be derived from adipose tissues surrounding the tumor, which undergo polarity shifts from M1 towards M2 phenotype, migrate into the tumor, become a part of the TME, proliferate in situ, and, in turn, promote tumor growth, invasiveness, proliferation, and EMT finally (Almendros et al., 2015; Almendros et al., 2014). The aforementioned studies also indicate that obesity-related chronic inflammation and local hypoxia may promote tumor progression via pathways similar to CIH-adipose tissue-TME. Therefore, CIH could change TME and influence OSA-associated lung cancer by macrophage polarity, exosome secretion, and immune escape.

CSCs are a subpopulation of cancer cells with self-renewal capacity, playing critical regulatory roles in tumorigenesis, tumor growth, recurrence, metastasis, EMT, and therapeutic responses (Fu et al., 2017). Cells with CSC potential can be identified via antibody-based sorting, tumor sphere formation, and other techniques (Nguyen et al., 2012), and these cells are capable of metastasizing from the primary site to distant organs to initiate metastatic tumors (Eramo et al., 2008; Dzobo et al., 2020). In lung cancer, CSCs regulate core signaling pathways including Janus kinase (JAK)/signal transducer and activator of transcription (STAT), nuclear factor κB (NF-κB), Notch, PI3K/AKT serine/threonine kinase, SHH, and Wnt/β-catenin, while also participating in TME remodeling and cancer drug resistance mechanisms (Heng et al., 2019).

In addition, studies showed that CSCs have an important role in the condition of CIH (Peng and Liu, 2015). Hao et al. demonstrated that CIH promotes lung cancer stemness by activating mitochondrial ROS (mtROS), a process partially mediated by CNC homolog 1 (Bach1) (Hao et al., 2021). Subsequent validation by the same research team revealed that CIH-induced upregulation of HIF-1α/ATAD2 exerts a significant regulatory effect on lung cancer stemness (Hao et al., 2022). Akbarpour’s team also confirmed that CIH enhances the expression of stemness markers, endowing tumors with stronger metastatic potential (Akbarpour et al., 2017). Additionally, CIH activates EMT-related transcription factors and promotes the dedifferentiation of cancer cells into CSCs by upregulating embryonic stem cell transcription factors such as OCT4, SOX2, and NANOG (Díaz-et al., 2021). Previous studies have also shown that CIH mediates the acquisition of CSC characteristics by regulating the TGF-β signaling pathway via paraspeckle component 1 (PSPC1) (Pengo et al., 2021).

At the immunoregulatory level, CIH-induced CSC-like properties are closely associated with impaired anti-tumor immune function: CIH upregulates the PD-1/PD-L1 pathway to inhibit CD8⁺ T cell cytotoxicity. Although CIH increases the number of CD8⁺ T cells, these immune cells—normally secreting granzyme B and perforin—exhibit impaired function, thereby promoting tumor growth and invasion (Akbarpour et al., 2017; Cubillos-Zapata et al., 2017). However, this mechanism remains controversial: Recoquillon et al. found that OSA did not alter exosomal PD-L1 expression or peripheral lymphocyte activity (Recoquillon et al., 2024), with core differences attributed to variations in PD-L1 expression carriers, immune cell targets, OSA pathophysiological features (CIH alone vs. combined with SF), and age stratification across studies. Future research should unify the detection dimensions of PD-L1 expression and immune cells, and conduct integrated analyses incorporating OSA pathophysiological characteristics and age factors to clarify the specific regulatory mechanism of this association.

Drug resistance is also closely linked to CIH-induced CSC-like properties. Gu et al. constructed a lung cancer stem cell (LCSC) model and a mouse model with tumors in situ and found that CIH exposure leads to cisplatin resistance; the tumor spheres formed from NSCLC cell lines were also identified in this condition (Gu et al., 2021). Except for cisplatin resistance, CIH directly induces resistance to doxorubicin in NSCLC (Song et al., 2006). Chemotherapy is a potential method in the therapy of lung cancer, but acquired cisplatin resistance has become a serious and primary problem in this course of treatment. Therefore, CSCs and their related pathway signals may be a new therapeutic target in treating OSA-associated lung cancer and chemoresistant OSA-associated lung cancer.

N6-methylation (m⁶A) is the most common internal modification found in mRNA within higher eukaryotes (Pan, 2013). The process is carefully managed by methylases (writers), demethylases (erasers), and proteins that recognize methylation (readers). Recent research has indicated that m⁶A modification could influence cell proliferation, metastasis, apoptosis, and cell death in cancers; thus, m⁶A has been proposed as a novel therapeutic and diagnostic target in cancers (Mobet et al., 2022; Khan and Malla, 2021). For example, overexpression of ALKBH5 (human AlkB homolog H5) could decrease the expression of cellular m⁶A level (Zheng et al., 2013), which belongs to the AlkB family of iron (II)/α-ketoglutarate (α-KG)-dependent dioxygenases (Kurowski et al., 2003).

At present, the role and mechanism of m6A modification in the occurrence and development of cancer are one of the hotspots in tumor biology research. m6A modification plays a pivotal role in the occurrence and development of lung cancer. Also, recent studies suggested that methylation could cause hypoxia in OSA. Chao et al. found increased ALKBH5 in lung cells (A549 and HCI-H522) under the condition of intermittent hypoxia (64 cycles of 5 min sustained hypoxia [1% O₂, 5% CO₂, and balanced N₂] and 10 min normoxia) compared with RA, while its inhibition repressed the growth and invasion of lung cancer under CIH; during this process, m6A levels were increased and FOXM1 was decreased, which suggests that ALKBH5 regulates FOXM1 mRNA modification and translation (Chao et al., 2020). Another study found that m6A demethylase ALKBH5 downregulates m6A modification on FOXM1 mRNA and promotes FOXM1 expression in patients with OSA-associated lung cancer, which could be a new sight for the diagnosis and treatment of patients with OSA-associated lung cancer.

DNA methylation is also a type of epigenetic modification that has an important role in respiratory diseases, such as lung cancer and OSA (Al-Yozbaki et al., 2022; Zhang et al., 2019). Cortese et al. found that exposure to CIH in mice enhances the release of circulating DNA into circulation, which carries distinctive epigenetic signatures that may characterize cell populations within the tumor that are more prone to shedding their DNA under CIH conditions (Cortese et al., 2015).

Some related factors, such as endothelial cell-specific molecule-1 (ESM1), HIF‐1α, vascular endothelial growth factor (VEGF), Bach1, COX-2, PGE2, and other factors, participated in this process. Several studies have explored the following pathways concerning the relationship between OSA and lung cancer, revealing the importance of CIH in the OSA state, affecting the development of lung cancer (Figure 1).

SF constructs an immunosuppressive microenvironment to directly promote lung cancer progression by regulating the function of TAMs and downstream signaling pathways. Studies have shown that SF can recruit TAMs and induce their polarization toward the pro-tumor M2 phenotype, while upregulating TLR4 expression on TAMs and activating the TLR4 signaling pathway (partially involving MYD88 and TRIF pathways) (Hakim et al., 2014). This process enhances matrix metalloproteinase (MMP) activity, accelerates lung cancer cell proliferation and invasion, and increases serum TNF-α levels to further strengthen immunosuppression (Xian et al., 2021). Additionally, SF downregulates the expression and activity of gp91phox in TAMs, reducing NADPH oxidase 2 (Nox2) activity and ROS production, impairing the anti-tumor function of TAMs and indirectly promoting tumor progression (Zheng et al., 2015).

SF induces oxidative stress by increasing tissue ROS levels, leading to DNA damage, and this effect is independent of enhanced inflammation. Research in colorectal cancer models has confirmed that SF can increase ROS content in colon tissue, resulting in 8-OHdG-related DNA damage, thereby increasing tumor number and enlarging tumor volume (Lee D. B. et al., 2023). This mechanism is also potentially applicable in lung cancer, suggesting that SF may provide an initial driving signal for lung cancer initiation by directly disrupting genomic stability.

SF mediates the transmission of pro-tumor signals between cells by altering the molecular cargo of circulating exosomes. Khalyfa et al. found that circulating plasma exosomes obtained from SF mice or OSA patients can enhance the proliferation and migration abilities of tumor cell lines (Khalyfa et al., 2016). Further studies have shown that SF exposure can induce mice to produce exosomes containing unique miRNAs (miR-5128, miR-5112, miR-6366), which can act as molecular carriers to regulate the cell cycle and immune escape of lung cancer cells. In addition, SF can promote the overexpression of lung cancer stem cell markers (CD133, CD44) through exosomes, maintaining tumor stemness and enhancing its malignant potential (Akbarpour et al., 2017).

SF synergistically promotes the formation of a lung cancer metastatic microenvironment by disrupting multi-system homeostasis. In a murine melanoma model, SF can alter lung tissue proteome expression, involving 43 key regulatory genes such as Lama2, Ptk2, and Grb2, focusing on core pathways including focal adhesion and hormone response. Meanwhile, SF disrupts gut microbiota composition, increases the Firmicutes/Bacteroidetes ratio, and abnormally regulates taxa such as Bacteroides and Desulfovibrio, indirectly promoting tumor metastasis (Xian et al., 2021). Additionally, sympathetic hyperactivity induced by SF can regulate inflammatory responses through β-adrenergic receptors, further amplifying pro-carcinogenic effects (Wheeler et al., 2021).

SF and CIH synergistically promote lung cancer progression through complementary mechanisms: CIH centers on hypoxia-related signaling pathways (e.g., HIF pathway), while SF focuses on immune microenvironment remodeling and neuro-inflammatory regulation. Notably, SF does not induce significant upregulation of the PD-1/PD-L1 axis in immune cells, nor does it produce a synergistic effect with CIH on this pathway (Cubillos-Zapata et al., 2020). However, SF can significantly amplify CIH-mediated lung cancer initiation and progression by strengthening immunosuppression, accelerating DNA damage, and promoting intercellular pro-tumor signal transmission. Together, they constitute the dual pathological drivers of OSA-promoted lung cancer.

As the most common subtype of NSCLC, lung adenocarcinoma mainly grows peripherally. Although it rarely directly compresses the central airways, it is prone to complications such as pleural metastasis and pleural effusion in advanced stages. These complications can indirectly interfere with the stability of respiratory rhythm by reducing thoracic compliance and impairing respiratory muscle contraction efficiency, providing a pathological basis for the occurrence of OSA. A cell experiment has shown that different lung adenocarcinoma cell lines [e.g., H522, H1437 (p53 mutant, EGFR wild-type), H1975 (p53 mutant, EGFR mutant)] exhibit certain differences in proliferation rates when exposed to CIH, suggesting that the hypoxic sensitivity of lung adenocarcinoma may be regulated by driver gene mutation status (Marhuenda et al., 2019). Animal experiments further confirmed that CIH can accelerate lung adenocarcinoma progression by altering components of the TME (Qi P. et al., 2023). However, clinical evidence for the association between the above complications and OSA is still scarce, and more clinical data are needed to support the mechanistic hypothesis.

The association between lung squamous cell carcinoma and OSA is driven by dual mechanisms, involving anatomical synergy and biological response differences. Anatomically, as a predominantly centrally located tumor, lung squamous cell carcinoma tends to invade or compress the main airways and mediastinum, causing airway stenosis and airflow limitation. This structural airway damage overlaps with the inherent airway collapse mechanism of OSA, which may not only increase the risk of OSA but also exacerbate its severity. Biologically, the association relies on hypoxia-mediated inflammatory infiltration and angiogenesis. Marhuenda et al. confirmed that the lung squamous cell carcinoma cell line H520 (p53 mutant, EGFR wild-type) exhibits a significantly faster proliferation rate than lung adenocarcinoma cell lines under CIH (Marhuenda et al., 2019). The core mechanism is related to the high dependence of lung squamous cell carcinoma on chemokine signaling pathways—CIH upregulates chemokine expression, enhancing the local invasive capacity of lung squamous cell carcinoma. Currently, there are relatively few specialized studies on this association, and the specific association strength and clinical significance between the two await verification by large-sample clinical cohorts.

As a highly malignant neuroendocrine tumor, SCLC is characterized by rapid proliferation and early extensive metastasis, with limited dedicated research on its association with OSA. This subtype often causes local invasive symptoms such as superior vena cava syndrome and recurrent laryngeal nerve palsy, directly leading to mechanical airway stenosis or abnormal respiratory neural regulation; the neuroendocrine factors it secretes may also interfere with the rhythm regulation of the respiratory center, theoretically having a pathological basis for inducing or exacerbating OSA. However, due to the poor prognosis and rapid progression of SCLC, clinical studies mostly focus on tumor treatment and survival, with extremely limited dedicated exploration of its association with OSA, and no direct evidence clarifying the correlation and association strength. In addition, a small-sample study involving 69 lung cancer patients showed that SCLC patients had higher apnea hypopnea index, oxygen desaturation index, and time with oxygen saturation <90% compared with adenocarcinoma and squamous cell carcinoma patients, with the proportion of moderate-to-severe OSA reaching 28%. However, statistical significance was not achieved due to limited sample size (only 8 SCLC patients) (Lee H. et al., 2023); clinical prognostic data also indicated that lung cancer subtype is an independent prognostic factor for OSA-associated lung cancer patients (HR = 1.043, 95% CI: 1.002–2.431, P = 0.038), with SCLC patients having significantly shorter overall survival than NSCLC patients, indirectly suggesting a potential specific association between the two (Liu W. et al., 2022).

EGFR mutation is a key regulatory factor for the sensitivity of lung cancer to OSA-related hypoxia. In vitro experiments have confirmed that this genotype of lung adenocarcinoma has no obvious response to OSA-related hypoxia (Marhuenda et al., 2019), possibly due to EGFR mutation impairing HIF-1α-mediated signal transduction. The EGFR signaling pathway can regulate the TGF-β/EMT pathway (Moustakas and Heldin, 2016; Cheng et al., 2022), which may synergize with the pro-invasive effect of OSA-induced TGF-β upregulation, but requires verification by functional experiments. In addition, patients often have high release of inflammatory factors such as IL-6 and TNF-α, which may indirectly increase OSA risk, and adverse reactions related to EGFR inhibitors may disrupt sleep. However, there is no specialized data supporting their direct association or the impact of CIH. OSA has a more significant impact on the malignant progression of EGFR wild-type NSCLC, with the core mechanism being OSA-induced upregulation of the co-expressed gene PDGFB (Wang et al., 2021). High PDGFB expression is closely associated with lymph node metastasis in patients with this genotype (Donnem et al., 2010; Don et al., 2011), suggesting that OSA may exacerbate the malignant phenotype by activating PDGFB-mediated angiogenesis and metastasis pathways.

CIH may exacerbate abnormal MAP2K3 gene expression (abnormal methylation of this gene is more common in this genotype (Park et al., 2008)), promoting tumor proliferation, invasion, and drug resistance by regulating pathways such as MAPK, with the mechanism to be verified. Meanwhile, this genotype of lung cancer is characterized by high invasiveness and a strong inflammatory phenotype, with elevated levels of pro-inflammatory factors in the tumor microenvironment, which may disrupt airway stability and increase OSA risk. However, the correlation between the two lacks specialized analysis, and the association strength and mechanism need further verification.

Accounting for 4%–6% of lung adenocarcinoma (Schneider et al., 2023), the unique stromal reaction and inflammatory characteristics of tumors may indirectly affect airway function, and side effects related to ALK inhibitors may interfere with sleep quality. Currently, there are no clinical or basic studies exploring its association with OSA, which is a complete data gap. Targeted explorations are urgently needed to clarify whether there is a specific association between the two.

Endothelin-1 and its receptors play a crucial role in CIH-induced cancer progression, exacerbating the malignant phenotype by promoting tumor cell proliferation, migration, angiogenesis, metastasis, and chemoresistance. A recent study confirmed that therapeutic blocking of endothelin receptors can effectively prevent CIH-induced tumor formation in both in vitro and in vivo models (Minoves et al., 2022), providing direct experimental evidence for anti-angiogenic therapy of OSA-associated lung cancer and promising to be one of the precise targeted strategies.

Vascular cell adhesion molecule-1 (VCAM-1) is a key biomarker for vascular microenvironment remodeling in OSA-associated lung cancer. A clinical cohort study showed that circulating VCAM-1 levels in OSA patients are significantly associated with cancer risk (Hirsch Allen et al., 2024). It promotes tumor invasion and metastasis by mediating the adhesion and transendothelial migration of tumor cells and endothelial cells (Schlesinger and Bendas, 2015; Dymicka-Piekarska et al., 2012); moreover, VCAM-1 levels in patients with OSA combined with melanoma are significantly higher than those in tumor patients without OSA (Dymicka-Piekarska et al., 2012), indicating its specific role in vascular infiltration of OSA-related tumors. Therefore, the development of VCAM-1-specific inhibitors or antibody drugs can inhibit tumor vascular infiltration and distant metastasis by blocking the interaction between tumor cells and vascular endothelium, which is particularly suitable for OSA-associated lung cancer patients.

In summary, anti-angiogenic therapy, by targeting the abnormal angiogenesis pathway mediated by OSA-related CIH, holds promise as an effective adjuvant treatment for OSA-associated lung cancer. This therapeutic strategy is particularly suitable for combination with CPAP, chemotherapy, or targeted therapy to further improve efficacy. However, the safety and effectiveness of relevant strategies still need to be verified by large-scale clinical trials, and the suitable populations among different lung cancer subtypes need to be clarified.

Endostatin is an endogenous anti-angiogenic glycoprotein hydrolyzed from the carboxyl terminal of extracellular matrix collagen (Poluzzi et al., 2016). It can achieve tumor microenvironment inhibition and vascular normalization recovery by inhibiting VEGF and its signaling pathway, and regulating factors such as HIF-1α, MMPs, and basic fibroblast growth factor (bFGF) (Limaverde-Sousa et al., 2014; Walia et al., 2015; Fukumoto et al., 2005; Li K. et al., 2018). Clinical studies have shown that circulating endostatin levels are elevated in OSA patients (HR = 1.45, 95% CI = 1.12–1.87, P = 0.005) (Hirsch Allen et al., 2024), which is speculated to be a compensatory response to the pro-angiogenic microenvironment induced by OSA (Ärnlöv et al., 2013), but a single elevation is insufficient to inhibit tumor progression. In the CIH-induced OSA-associated lung cancer mouse model, endostatin can reduce cell proliferation and angiogenesis by inhibiting VEGF expression (Zhang et al., 2019), suggesting its potential therapeutic value. Given the complexity of angiogenesis imbalance in OSA patients, endostatin needs to be used in combination with other anti-angiogenic drugs such as VEGF inhibitors to enhance the blocking effect on abnormal angiogenesis and improve therapeutic efficacy.