Current status and advances in research on the impact and mechanisms of atmospheric pollutants on gastric cancer: a narrative review

Introduction

Globally, cancer has emerged as a pivotal factor in mortality rates. Research (1) indicates that malignant tumors of the digestive system account for over one-third of all cancer-related deaths. Gastric cancer (GC), ranking as the fifth most common cancer worldwide and the fifth leading cause of cancer-related fatalities (2), poses a significant threat to human health. Notably, there is a marked geographical disparity in the incidence of GC, with higher rates observed in East Asia, Eastern Europe, and South America, contrasted by relatively lower rates in North America and most regions of Africa (3).

According to relevant studies (4,5), the occurrence, development, and heterogeneity of GC are the result of the interaction between environmental and genetic factors, with environmental factors playing a dominant role and genetic factors accounting for 28% of the influence. Numerous studies have indicated that (6,7), Helicobacter pylori (H. pylori) infection, dietary habits, alcohol consumption, tobacco use, overweight, and metabolic disorder and socioeconomic conditions are among the environmental risk factors for GC. In recent years, with the global climate change, the association between atmospheric pollutants and GC has increasingly attracted the attention of academia.

Atmospheric pollutants, including particulate matter (PM), nanoparticles, bioaerosols, and specific chemical substances, pose significant hazards to ecological environments and human health. Research by Anderson et al. (8) and Liao et al. (9), among others, has demonstrated that atmospheric pollutants can cause damage to various systems, including respiratory, cardiovascular, reproductive, endocrine, and digestive systems. As a long-term environmental factor closely associated with human beings, some studies (10) have indicated that atmospheric pollutants may influence the development of GC. Currently, the etiological mechanisms by which atmospheric pollutants contribute to GC remain incompletely elucidated. Therefore, this study aims to explore the association and underlying mechanisms between atmospheric pollutants and GC. We present this article in accordance with the Narrative Review reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1877/rc).

Methods

A literature search was conducted in PubMed and Web of Science databases using the keywords “stomach neoplasms” OR “gastric cancer” OR “stomach cancer” OR “gastric carcinoma” AND “air pollutants” OR “air pollution” OR “atmospheric pollutants” OR “air pollutants” OR “ambient” OR “PM” OR “Gaseous pollutants” OR “PAHs”. The secondary references cited in articles obtained from the PubMed and Web of Science search were also retrieved. The methodology of the search is summarized in Table 1.

Overview of atmospheric pollutants

Atmospheric pollutants, as significant environmental risk factors for GC, primarily include PM (PM₁, PM_2.5, PM₁₀), gaseous pollutants [sulfur oxides (SOx), carbon oxides (COx), nitrogen oxides (NOx), O₃], polycyclic aromatic hydrocarbons (PAHs), and persistent organic pollutants (POPs) (11) (Table 2). These pollutants are released through various pathways such as industrial emissions, vehicular exhaust, and fuel combustion. The composition of these pollutants has become increasingly complex with the process of urbanization. Studies have shown (12-16) that atmospheric pollutants can enter the stomach directly or indirectly through respiration, diet, and bile reflux, thereby affecting the gastric microenvironment and increasing the risk of GC.

Epidemiological studies on atmospheric pollutants and GC

PM and GC

PM, particularly PM_2.5, PM₁₀, and PM₁, constitutes the most closely associated atmospheric pollutants with GC. A cohort study in Jiangsu Province revealed that long-term exposure to PM_2.5 increases the risk of GC by 2.8% (17). A cohort study in Taiwan found that long-term exposure to PM_2.5 elevates the mortality risk of gastrointestinal cancers by 9% (18). A study in Brazil examining the association between wildfire-related PM_2.5 exposure and cancer mortality rates demonstrated that for every 1 µg/m³ increase in wildfire-related PM_2.5 concentration, the relative risk (RR) of GC mortality increased by 3% (19). The study also explored potential mechanisms underlying this relationship, suggesting that PM_2.5 induces oxidative stress, genotoxicity, or inflammation, thereby accelerating cancer progression (20,21). Additionally, PM_2.5 may infiltrate the digestive tract, altering immune responses and affecting gut microbiota and epithelial cells (22). A cohort study in Northwest China indicated that exposure to PM₁ was associated with a 2.3% increase in GC incidence in regions with an overall age-standardized incidence rate exceeding 40% (12). The toxicity of PM is linked to its heavy metal content (e.g., arsenic, cadmium), which can promote GC development through mechanisms such as oxidative stress, inflammatory responses, and DNA damage, consistent with previous findings. A Korean epidemiological survey (23) revealed that male participants exposed to dust experienced a 23.9% increased risk of GC [95% confidence interval (CI): 19.9–27.5], and individuals with occupational exposure to dust had a higher risk of GC compared to the general population. Lee et al. (24) conducted a systematic review and meta-analysis on the association between exposure to crystalline silica and GC, reporting an effect size of 1.25 (95% CI: 1.18–1.34) based on 20 cohort studies and 9 case-control studies. Another systematic review and meta-analysis yielded similar findings (25): occupational exposure to silica was associated with an increased risk of GC, with a pooled standardized incidence ratio of 1.35 (95% CI: 1.21–1.51, P<0.001). However, other cohort studies have yielded different results. A large European cohort study found no significant association between long-term exposure to PM_2.5 and GC incidence (26). A prospective cohort study using the UK Biobank revealed no significant association between PM_2.5 exposure and gastrointestinal cancers (27). The specific associations between PM exposure and GC incidence and mortality require further exploration through additional epidemiological studies.

Gaseous pollutants and GC

Gaseous pollutants encompass categories such as SOx, COx, NOx, O₃, and halogen compounds. These substances can contribute to the pathogenesis of GC through systemic inflammation and oxidative stress. Current epidemiological studies on the correlation between gaseous pollutants and GC are limited, yet some have elucidated relevant associations. A prospective cohort study by Yang et al. (28) demonstrated that exposure to SO₂ and NO₂, with their conversion products, inorganic sulfates and nitrates, being integral components of PM_2.5, is associated with a heightened incidence of gastrointestinal cancers. Conversely, a large-scale cohort study in Europe (26,29) indicated a negligible association between long-term environmental NO₂ exposure and GC occurrence.

Following the exploration of the carcinogenic effects of oxides in related studies, ozone, as a typical secondary pollutant of photochemical origin, has gradually garnered attention in recent years despite limited evidence of its carcinogenic potential. A nationwide case-crossover study in Brazil revealed that a three-day exposure to an increase of 10 µg/m³ in ozone levels was associated with a 1.29% rise in GC mortality (30).

PAHs and GC

PAHs are a large class of chemical compounds consisting of 2–7 fused aromatic rings. Due to their widespread distribution in air, soil, and water sources, numerous studies have demonstrated that PAHs are teratogenic, carcinogenic, and mutagenic. A matched case-control study conducted in Taiwan (31) indicated that regions with high traffic-related air pollution exhibited higher GC mortality compared to areas with lower pollution levels, which may be attributed to the presence of benzene and other hydrocarbons emitted by vehicles. A large-scale occupational benzene exposure study (32) conducted in Shanghai, China, investigating the association between benzene exposure and cancer risk among Chinese men revealed that benzene exposure exceeding 550 mg/m³ was associated with an increased risk of GC (hazard ratio =1.4, 95% CI: 1.0–1.9), with a linear dose-response relationship (P_linear =0.023). The study by Zhao et al. (33) revealed that individuals with high benzo[a]pyrene-7,8-dihydrodiol-9,10-oxide-albumin adduct (BPDE-Alb) exposure exhibited a 2.14-fold increased incidence of GC compared to those with low exposure; further investigation suggested that alterations in aryl hydrocarbon receptor (AhR) and epidermal growth factor receptor (EGFR) receptors, along with changes in cell proliferation and apoptosis pathways, may be involved in the carcinogenic process. Benzo[a]pyrene (BaP), a type of PAH, can enter the human body through diet or respiration. A study by Wei et al. (34) demonstrated that BaP may promote the proliferation and metastasis of GC cells by upregulating the expression of MMP9 and c-myc via the AhR and ERK signaling pathways.

POPs and GC

POPs are a class of synthetic organic compounds characterized by high toxicity, environmental persistence, bioaccumulation, and long-range transport capabilities (35). They can cause widespread adverse effects on the environment and living organisms, with their carcinogenic, teratogenic, and mutagenic “three-carcinogenic” effects being particularly concerning. It is important to clarify that for the general population, dietary intake (through contaminated food and water) represents the primary route of human exposure to POPs (36). However, this does not diminish the relevance of incorporating POPs into studies linking atmospheric pollutants and GC, as the atmosphere serves as a critical hub for the global circulation and multi-medium environmental migration of POPs. POPs’ semi-volatile nature enables long-range atmospheric transport, leading to environmental contamination upon deposition (37). This process constitutes the initial critical step for POPs to enter and accumulate within the food chain, ultimately posing threats to human health. Studying atmospheric POPs is essential for understanding their global trends and assessing indirect risks associated with GC.

Epidemiological evidence from multiple studies has revealed an association between exposure to POPs and the risk of GC. According to exploratory research conducted by Martine Perrot-Applanat’s team (38), diffuse GC patients exhibited significantly elevated levels of POPs such as polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), and polybrominated biphenyls (PBBs) in their omental adipose tissue compared to healthy controls. A retrospective study by Bertazzi et al. (39) on an industrial accident in Italy revealed that over a decade following dioxin exposure, the female GC mortality rate increased by 1.4 times compared to the unexposed group. Prince et al.’s study of 14,458 workers exposed to PCBs found that the standardized mortality rate for GC among male workers increased by 53% compared to the unexposed group (40). An epidemiological survey (41) revealed that exposure to insecticides and herbicides was associated with an increased adjusted odds ratio for diffuse-type GC, with an odds ratio of 1.66. Some studies (42) have identified multiple exposure pathways of per- and polyfluoroalkyl substances (PFAS) among firefighters during their work, such as aqueous film-forming foams, air, and dust at fire scenes. Epidemiological investigations indicate (43) that this population has a significantly higher risk of gastrointestinal cancers compared to the general population, with a RR of 1.14. Additionally, an analysis of 24 PFAS analytes in serum and tumor samples from patients with hepatobiliary and gastrointestinal malignancies revealed that at least one PFAS analyte was detected in 97% of serum samples and 41% of tumor samples (44). However, another meta-analysis found no association between PFAS exposure and GC (45). Therefore, more rigorous studies are needed to precisely quantify PFAS, expand the range of compounds examined, and increase sample sizes for specific cancers.

Although dietary intake is the primary route of exposure to POPs, the atmosphere plays an indispensable role as the initial driver of their global distribution and entry into food chains. Investigating POPs in the atmosphere holds significant public health importance, enabling a fundamental understanding of their environmental fate, assessment of their potential to contaminate food, and ultimately, mitigation of their long-term risk for GC.

Mechanisms of atmospheric pollutants on the pathogenesis of GC

Inflammatory response and oxidative stress

The underlying molecular mechanisms by which atmospheric pollutants contribute to GC remain largely unexplored. However, mounting evidence suggests that inflammatory responses and oxidative stress may constitute pivotal factors in the pathogenesis of GC induced by air pollution.

Atmospheric pollutants induce inflammatory responses

The activation of a systemic inflammatory state is considered a critical underlying pathway mediating the health impacts associated with exposure to gaseous atmospheric pollutants. Gaseous pollutants, such as NO₂, can promote lipid peroxidation in gastric tissues through systemic inflammatory responses, thereby compromising mucosal barrier function. Previous studies have shown (46,47) that ozone exposure leads to elevated concentrations of various inflammatory mediators, including tumor necrosis factor-α (TNF-α) in human alveolar cells and inflammatory cytokines such as interleukin (IL)-6 and IL-8 in human airway epithelial cells. Zhang et al. (48) and Goodman et al. (49) further demonstrated, through both human and animal studies, that ozone exposure induces oxidative damage to cells and the airway lining fluid, triggering immune-inflammatory responses in the lungs. These elevated inflammatory mediators can disseminate to the gastric mucosa via the circulatory system (14,16), thereby inducing chronic gastritis.

For PM, inflammation has been demonstrated to be closely associated with the majority of adverse health effects attributed to PM (50). A small animal study by Zheng et al. (51) demonstrated that exposure to PM_2.5 can induce neutrophilic alveolitis and bronchitis, and synergistically enhance the levels of IL-4, IL-12, and IL-17 when combined with ovalbumin (OVA), thereby promoting allergic inflammation. Feng et al. (50) synthesized findings from multiple experiments, revealing that both in vivo and in vitro, PM-induced inflammatory responses lead to increased mRNA expression and protein secretion of EGF-like growth factors in airway epithelial cells. These growth factors, acting as EGFR ligands, are integral to both pro-inflammatory and repair responses. The elevated levels of these ligands subsequently promote the release of neutrophil-macrophage colony-stimulating factor by bronchial epithelial cells, sustaining the PM-induced pro-inflammatory response in the airways and facilitating bronchial remodeling. In a mouse study conducted by Ran et al. (52), prolonged exposure to low-dose PM_2.5 was found to result in a decline in the number of tight junction proteins, significantly compromising the integrity of the gastrointestinal barrier. This may further activate inflammatory caspases via the TLR2/5-MyD88-NLRP3 signaling pathway, thereby contributing to damage of the gastrointestinal mucosa.

Inhalation of environmental pollutants (SOx, COx, NOx) exerts an additional systemic pro-inflammatory effect, as pro-inflammatory cytokines generated in the lungs following pollution exposure can enter the systemic circulation, leading to elevated serum mediators [e.g., IL-6, IL-1β, granulocyte-macrophage colony-stimulating factor (GM-CSF)], increased numbers of neutrophils and platelets, as well as endothelial dysfunction and arterial vasoconstriction (53,54). The sustained elevation of inflammatory mediators promotes abnormal proliferation of gastric epithelial cells, inhibits apoptosis, and thereby increases the risk of carcinogenesis (Figure 1).

Figure 1 Mechanistic diagram of atmospheric pollutants inducing gastric cancer via inflammatory response. Atmospheric pollutants such as O₃, NOx, SOx, and COx enter the human body through respiration and reach the lungs. The inflammatory mediators produced, including IL-6 and IL-8, are transported via the circulatory system to the gastric mucosa. This leads to abnormal proliferation of gastric epithelial cells and a reduction in apoptosis, ultimately contributing to the development of gastric cancer. COx, carbon oxides; IL, interleukin; NOx, nitrogen oxides; SOx, sulfur oxides; TNF-α, tumor necrosis factor-α.

A study on the co-exposure of PAHs and metals leading to lung function impairment indicates that leukocytes can mediate the pulmonary damage caused by exposure to PAHs and metals (55), with further research uncovering potential underlying mechanisms. Additionally, previous animal studies have demonstrated that chronic exposure to PAHs induces cytochrome P-450 family enzymes in rats, thereby augmenting oxidative stress and inflammatory responses (56,57).

Atmospheric pollutants inducing oxidative stress

Studies have demonstrated that PM₁, due to its extremely small particle size, can penetrate deep into the alveolar region of the human lung and subsequently enter the gastrointestinal system via mucociliary clearance. The heavy metals and PAHs it carries can induce oxidative stress in gastric mucosa, leading to DNA damage (12). Concurrently, relevant research (58) indicates that exposure to PM_2.5 disrupts the body’s inherent balance between oxidative and antioxidative states. For instance, PM_2.5 exposure significantly elevates malondialdehyde (MDA) levels while reducing the activity of total superoxide dismutase (T-SOD) (59). Additionally, PM_2.5 exposure inhibits the expression of Nrf2 protein and its downstream heme oxygenase-1 (HO-1) in the lungs of rats with chronic obstructive pulmonary disease (COPD) (60). At the cellular level, mitochondria, as the primary site for endogenous reactive oxygen species (ROS) production, experience disruption of redox balance upon PM_2.5 exposure, leading to abnormal mitochondrial structure changes and a sustained rise in ROS levels (61). ROS, serving as a critical intermediate signaling molecule, activates a series of signaling pathways including nuclear factor kappa-B (NF-κB), toll-like receptor (TLR), and mitogen-activated protein kinase (MAPK) (62). Once activated, these pathways interfere with the normal function of cellular signal transduction proteins, ultimately triggering the initiation of inflammatory responses (63). Notably, metallic components in PM, such as cadmium, can generate ROS through the process of oxidative stress induction, causing DNA damage in gastric mucosal cells, increasing the risk of gene mutations, and potentially leading to cellular carcinogenesis (64).

In the context of PAHs, a study by He et al. (65) has demonstrated that PAH exposure significantly elevates the levels of ROS, disrupting the intracellular redox balance and resulting in DNA damage and endothelial dysfunction. The interplay between ROS and inflammatory cytokines, such as TNF-α, further exacerbates oxidative stress and inflammatory responses. ROS can directly attack DNA bases, leading to double-strand breaks and impairments in mismatch repair mechanisms, which in turn activate proto-oncogenes and inactivate tumor suppressor genes, thereby driving the onset of GC (Figure 2).

Figure 2 Mechanistic diagram of atmospheric pollutants inducing gastric cancer via oxidative stress. Atmospheric pollutants such as PM and PAHs lead to elevated ROS levels within mitochondria, subsequently causing DNA damage and double-strand breaks. Intracellular inflammatory mediators, including IL-6 and IL-8, can activate the NF-κB signaling pathway, resulting in the expression of cell proliferation and anti-apoptotic genes, collectively contributing to the development of gastric cancer. IL, interleukin; ILR, interleukin receptor; ILS, interleukin subtype; NF-κB, nuclear factor kappa-B; PAHs, polycyclic aromatic hydrocarbons; PM, particulate matter; ROS, reactive oxygen species; TNF-α, tumor necrosis factor-α.

Inflammatory response and oxidative stress on GC-associated genes and cells

Inflammatory response and oxidative stress do not act independently but rather influence and synergistically promote the development of GC (66). ROS, as the primary effector molecules of oxidative stress, not only directly damage the DNA of gastric mucosal cells, inducing gene mutations, but also activate transcription factors such as NF-κB and AP-1, thereby regulating the expression of over 500 genes, including pro-inflammatory cytokines, growth factors, and cell cycle regulatory molecules. Under persistent stimulation from chronic gastric inflammation (such as H. pylori infection or chronic gastritis), ROS produced by inflammatory cells exacerbate oxidative stress levels. This oxidative stress further activates inflammatory responses through the release of damage-associated molecular patterns (DAMPs), creating a vicious cycle. In this process, inflammatory mediators such as TNF-α, IL-1, and IL-6 promote the expression of GC-related genes (such as those involved in cell proliferation and anti-apoptosis) via signaling pathways like NF-κB while also feedback-increasing ROS production. The interaction between oxidative stress and inflammation is a continuous dynamic process during which there are significant changes in the expression patterns of GC-related genes. These changes create a microenvironment conducive to tumor cell proliferation, enhancing their survival capabilities and promoting their acquisition of stronger migratory and invasive characteristics (Figure 2). Simultaneously, these changes influence tumor sensitivity to treatment, collectively driving the initiation, progression, and malignant transformation of GC. Therefore, elucidating this complex network mechanism is crucial for developing novel strategies for prevention and treatment.

Abnormalities in immune regulation

Impact of atmospheric pollutants on the immune system

Atmospheric pollutants can also promote the development of GC by impairing the human immune system. A study by Karavitis et al. (67) found that macrophages containing pollutant particles (PM₁₀) exhibited significantly compromised functionality, with a substantial reduction in their ability to phagocytose other particles and produce cytokines, whereas macrophages in the same lymph nodes devoid of particles remained unaffected. Similarly, a study by Ural et al. (68) revealed that the uptake of particles by macrophages directly influences their phagocytic function, leading to a reduced immune surveillance, which in turn weakens the body’s ability to monitor and eliminate abnormal cells and cancer cells within the gastric mucosa. Following several epidemiological studies, an animal experiment by Mutlu et al. (69) demonstrated that mice administered high doses of PM exhibited increased intestinal permeability (reduced expression of ZO-1 tight junctions), along with elevated IL-6 expression and gastrointestinal epithelial cell apoptosis. For inhalable atmospheric pollutants such as SOx, NOx, and COx, an immunoglobulin assay in a human population (70) revealed that children in heavily polluted areas had lower levels of IgA and IgM compared to those in lightly polluted areas, while IgG and IgE levels were higher in the former, indicating that inhalable atmospheric pollutants have a certain impact on immune function.

Dysfunction of immune surveillance

Current research evidence indicates that the immune system possesses a critical function known as immune surveillance. This function enables the immune system to identify and eliminate cells that have undergone malignant transformation within the body, thereby preventing tumor development. The immune system plays a pivotal role in tumor progression, invasion, metastasis, immune evasion, and therapeutic resistance. Within the tumor immune microenvironment, multiple cells and factors concurrently exert antitumor effects. Among tumor-associated macrophages, M1-like macrophages can reduce the number of tumor cells through phagocytosis and present tumor-induced antigens to T cells, demonstrating potent antitumor activity (71). Additionally, M1-like macrophages significantly upregulate the expression of major histocompatibility complex class II molecules and co-stimulatory molecules (such as CD80 and CD86), enhancing antigen presentation and subsequently activating tumor-specific T cell responses. A study by Zhuang et al. (72) demonstrated that preconditioning GC-associated macrophages with matrine upregulated the expression of Granzyme-B, TNF-α, and perforin, thereby increasing the proliferation and cytotoxic function of CD8 T cells. Furthermore, it downregulated exhaustion markers of CD8 T cells such as PD-1, Tim-3, and Lag-3, reshaping the GC immune microenvironment. BaP, a representative PAH, is widely present in atmospheric pollutants (e.g., vehicle exhaust, industrial emissions) and smoked/grilled foods. BaP can influence immune cells through the AhR pathway. Upon entering the human body, BaP binds to AhR and activates it, subsequently regulating the expression of a series of genes. Within immune cells, this activation impairs the function of dendritic cells. As key antigen-presenting cells within the immune system’s structure, dendritic cells play an indispensable role. Dysfunction of these cells impairs the effective presentation of tumor antigens, making it difficult for T cells to recognize tumor cells and thereby weakening immune surveillance capabilities.

Metabolism

Recent studies have revealed that atmospheric pollutants can influence the initiation and progression of GC through metabolic reprogramming. A study by Liang et al. (73) found that long-term exposure to atmospheric pollutants such as PM_2.5, NO₂, and O₃ can significantly alter the blood metabolome, including increased levels of lysophosphatidylcholines (lysoPCs) and tryptophan metabolites, as well as decreased levels of antioxidant metabolites. These metabolic changes may promote oxidative stress, chronic inflammation, and lipid metabolic disorders, thereby activating GC-related signaling pathways and facilitating tumor progression. Moreover, long-term exposure to PM₁₀ has been observed to alter purine and pyrimidine metabolite profiles, potentially contributing to tumorigenesis through mechanisms involving DNA damage and repair processes. PM in atmospheric pollutants, along with SOx and NOx, can directly adsorb or chemically transform heavy metals such as chromium, arsenic, and cadmium. These metals can interfere with metabolic homeostasis through multiple pathways and promote the development of GC (74). Arsenic exposure can disrupt the gastric mucosal barrier, induce oxidative stress and lipid peroxidation, inhibit glutathione metabolism, leading to impaired DNA damage repair functions. Furthermore, there is a synergistic effect between heavy metals and H. pylori. Their combined action can impair local mucosal barrier function in the stomach and promote each other’s colonization on the gastric mucosal surface. This synergy intensifies oxidative stress responses and triggers local inflammatory reactions in the stomach tissue. Through a series of pathological processes—including DNA damage and disruption of cell signaling pathways—this interaction ultimately accelerates abnormal cell proliferation.

Recent studies have revealed that co-exposure to arsenic and BaP can significantly enhance carcinogenic effects through synergistic metabolic interference. A study by Xie et al. (75) found that co-exposure to arsenic/BaP upregulates the expression of integrin α4 (ITGA4) in human bronchial epithelial cells, which subsequently stabilizes the SUFU protein (a key inhibitor of the Hedgehog signaling pathway) by inhibiting the PI3K/Akt signaling pathway, leading to aberrant activation of the Hedgehog pathway. This ultimately enhances cancer stem cell-like properties and tumorigenicity. These findings may provide further insights into GC research.

Gut microbiota

In recent years, research on the gut microbiota has seen a marked increase. Studies have shown that long-term exposure to PM_2.5 can lead to alterations in gut microbiota structure (76). Recent studies have revealed that atmospheric pollutants can indirectly disrupt the balance of gut microbiota through the “gut-lung axis” or “multi-organ interactions”, thereby becoming a critical regulatory factor in the development of GC (14,16).

Chronic exposure to PM_2.5 has been found to significantly reduce the expression of intestinal tight junction proteins (ZO-1, occludin), leading to increased intestinal mucosal permeability. This disruption of barrier function is closely associated with the abnormal activation of the TLR2/5-MyD88-NLRP3 inflammasome pathway: the dysbiosis induced by PM_2.5 in the gut microbiota can activate the MyD88 signaling pathway through pattern recognition receptors TLR2/5. This activation further promotes the assembly of the NLRP3 inflammasome, resulting in the release of pro-inflammatory cytokines such as IL-1β and IL-18, thereby establishing a chronic low-grade inflammatory microenvironment.

Notably, emerging evidence suggests that atmospheric pollutants may indirectly compromise gut barrier integrity and exacerbate inflammation by inducing vitamin D deficiency. Air pollutants, particularly PM_2.5, can scatter and absorb ultraviolet B (UVB) radiation, thereby reducing cutaneous synthesis of vitamin D (77,78). Vitamin D is a critical regulator of gut homeostasis. It promotes the expression of tight junction proteins (79). Furthermore, vitamin D exhibits significant anti-inflammatory effects, partly through upregulating glutathione levels (80). Additionally, vitamin D enhances innate immunity by inducing antimicrobial peptides like cathelicidin (LL-37), which plays a role in defending against pathogens, including H. pylori (81). Given that H. pylori infection is a major risk factor for GC (82), and vitamin D status can influence the host response to this infection, a pollutant-induced vitamin D deficiency might create a permissive environment for H. pylori-associated carcinogenesis.

Such a chronic inflammatory state, whether directly from pollutant-induced dysbiosis or indirectly from a compromised barrier and vitamin D deficiency, can induce DNA damage in gastrointestinal mucosal epithelial cells, potentially leading to gastric carcinogenesis (52). Studies have shown (83) that PAHs and halogenated aromatic hydrocarbons (HAHs) exert their toxicity and carcinogenicity by interacting with the gut microbiota and activating the transcription factor AhR. A study published in Nature (84) demonstrated that gut microbiota can metabolize nitrosamine compounds such as N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) into N-butyl-N-(3-carboxypropyl)-nitrosamine (BCPN), which can form DNA adducts and induce bladder cancer. However, mechanisms by which atmospheric pollutants interact with gut microbiota to promote GC, including the potential mediating role of vitamin D deficiency, remain to be further elucidated through additional research.

Heredity

GC and heredity

The onset of GC is a multifaceted process involving multiple steps and factors, fundamentally resulting from the interplay between genetic susceptibility and environmental influences. In the molecular mechanisms underlying the development of GC, genes play a pivotal role. A multitude of gene types associated with GC have been identified, encompassing proto-oncogenes, tumor suppressor genes, DNA repair genes, immune-related genes, and metabolic enzyme-associated genes. Research indicates that sporadic GC constitute the majority in clinical settings, with only approximately 5–10% of cases exhibiting familial hereditary traits. Hereditary diffuse gastric cancer (HDGC) was the first type of GC identified with a hereditary predisposition (85). As an autosomal dominant disorder, its pathogenesis is primarily attributed to mutations in the CDH1 gene, which encodes for cell adhesion molecules. Such mutations lead to the loss of cell adhesion functions, significantly elevating risks of cellular proliferation, invasion, and metastasis (86). Peutz-Jeghers syndrome (PJS), on the other hand, is a rare hereditary condition characterized by gastrointestinal polyposis, mucocutaneous pigmentation, and an increased risk of various cancers (87). Previous studies have confirmed that PJS patients harbor germline mutations in the serine/threonine kinase 11 (STK11) gene (88). These mutations disrupt the normal regulatory mechanisms governing cell growth and division, giving rise to PJS-associated symptoms and substantially elevating the risk of gastrointestinal cancers in affected individuals compared to the general population.

Mechanistic studies on the atmospheric pollution-genetic interaction in GC

Previous research on the relationship between atmospheric pollutants and GC has primarily focused on epidemiological surveys and laboratory studies. Recently, there has been a rise in systematic, interdisciplinary emerging disciplines represented by environmental oncology. This field leverages cutting-edge scientific technologies and methodologies to investigate the mechanisms of carcinogenesis and to conduct early prevention and intervention for tumors. Technologies such as molecular epidemiology, high-throughput omics, big data analytics, bioinformatics, and gene-environment interaction studies are utilized to explore specific mechanisms at the genetic level.

The International Agency for Research on Cancer (IARC) has classified BaP as a group 1 carcinogen. An epidemiological study (89) reported that occupational exposure to procarcinogens, which are metabolically activated by cytochrome P450 enzymes through the AhR, leads to increased GC mortality. The AhR-associated cytochrome genes include P450 1A1 (CYP1A1) and P450 1B1 (CYP1B1). BaP, a well-known AhR pollutant ligand, has been shown by Perrot-Applanat and colleagues in a 2024 study (15) to significantly increase the expression of CYP1A1 and IL-1β (IL1B) in the poorly differentiated KATO III epithelial cell line, with moderate increases in UGT1, NQO1, and the AhR repressor (AhRR), thereby promoting the development of diffuse GC. Furthermore, continuous exposure of gastric epithelium to exogenous AhR ligands and the binding of various ligands to strongly activate the AhR likely represent a central process in GC development. CYP1A1 and CYP1B1 play pivotal roles in tumor development and the activation of procarcinogenic compounds such as BaP (90-95), with the activated AhR potentially contributing to tumor-stroma interactions in diffuse GC through CYP1A1 and CYP1B1, thereby facilitating tumor progression.

Research challenges and future prospects

Limitations

Environmental factors contribute to approximately 70–90% of cancer incidence (5,96), however, research on the carcinogenic effects of ambient atmospheric pollutants still faces numerous challenges and limitations. At the level of exposure assessment, these limitations are particularly pronounced. The sources of pollutants are extensive and complex. Although IARC has classified numerous air-related carcinogens, some compounds remain unclassified and require further exploration. Additionally, insufficient analysis of exposure pathways, unclear mechanisms of pollutant synergism, and a lack of long-term follow-up data hinder the precise quantification of cancer risk (97). From an experimental research perspective, current experimental models differ significantly from human conditions. Whether through animal experiments or in vitro studies, it is difficult to fully replicate real-world human exposure scenarios. The absence of human-based experimental data further impedes a comprehensive understanding of the carcinogenic mechanisms associated with atmospheric pollutants (98).

In the field of epidemiological research, significant shortcomings persist. The absence of randomized controlled trials and large-scale observational population studies means that single-exposure measurements alone cannot accurately reflect the cumulative lifetime exposure effects on individuals. Moreover, the uneven distribution of cancer control resources globally poses a constraint on the further advancement of research in this area. Assessments of cancer research expenditures in Europe, the United States, and Canada reveal that while total spending on cancer research ranges between 25% and 45%, expenditures on cancer prevention are limited to between 2% and 9%. Significant disparities exist both between and within countries in terms of cancer control planning and implementation, such as the enforcement of tobacco control measures (99), which further hinders progress in research.

Directions for future research

Interdisciplinary integration research

Future research in environmental oncology will frequently necessitate interdisciplinary integration, leveraging the convergence of clinical medicine, basic medicine, preventive medicine, molecular biology, and bioinformatics to delve deeply into the effects of atmospheric pollutants on GC and the mechanisms of environmental-genetic interactions. Simultaneously, technologies such as genomics, metabolomics, and exposomics will be employed to assess the impacts of air pollutant exposure, evaluate the toxic effects induced by these pollutants, and elucidate the molecular characteristics of GC under such exposure conditions. According to Li et al. (100), studies focusing on genomics, metabolomics, and exposomics respectively have collectively advanced our understanding of tumor progression at various levels. Moving forward, the trend toward multidisciplinary development is undoubtedly poised to shape the future trajectory of environmental oncology.

Longitudinal large-scale population cohort study

In the context of atmospheric pollutant exposure, current studies on the relationship between atmospheric pollutants and GC exhibit certain limitations. The accurate assessment of individual’s true exposure levels is challenging using only short-term or localized monitoring data. By conducting long-term, large-scale, multi-regional cohort studies, and comparing exposed and non-exposed groups, it is possible to more accurately evaluate the relationship between long-term exposure and disease, thereby more precisely determining the association between atmospheric pollutant exposure and GC. Long-term follow-up can capture the lag effect of environmental exposure and the changing patterns of gastric precancerous lesions, such as the transformation from chronic atrophic gastritis to GC (101).

Research on prevention and intervention strategies

At present, research on preventive and intervention strategies targeting atmospheric pollutant exposure and genetic susceptibility to GC is insufficient, necessitating further studies to develop personalized prevention and treatment strategies tailored to specific genetic backgrounds. To reduce pollutant exposure, measures such as promoting air purification technologies and optimizing urban planning can be employed to minimize contact time with pollutants, thereby decreasing overall exposure levels. A study (102) conducted in northern China revealed that mild to moderate air pollution persists during the winter heating season. Bacterial aerosols reached their highest concentrations during moderate pollution episodes, rather than during severe or heavy pollution periods, when PM_2.5 may carry substantial bacterial loads, particularly including genera of opportunistic pathogens. Therefore, effective measures should be implemented to mitigate health risks associated with bioaerosols during moderate pollution periods. Furthermore, inland and coastal cities should adopt distinct air quality management strategies; for instance, when severe pollution occurs in inland cities, coastal cities should also activate bioaerosol risk alerts during moderate pollution episodes. The National Institute for Occupational Safety and Health in the United States has developed an automated coding system based on the 1990 Census Bureau codes, which is used for categorizing “industry” and “occupation”. By inputting patients’ work information, industry, and occupation details into electronic health records, this system provides robust support for occupational health monitoring (103). Specifically, regular medical surveillance, organized health check-ups, and the implementation of early prevention and control measures can effectively reduce occupational exposure levels. In the field of GC prevention and control, for types of GC with genetic predisposition, risk screening using genetic testing technology can be employed, and personalized prevention strategies can be formulated accordingly. Notably, emerging DNA methylation detection technologies hold significant promise, and in the future, it is anticipated that environmental tumor warning markers could be developed based on DNA methylation characteristics, enabling early intervention and precise prevention and control of GC (104).

Conclusions

Atmospheric pollutants can promote the occurrence and development of GC through pathways such as inflammatory response, oxidative stress, immune regulation, metabolism, and gut microbiota modulation. Current research has achieved certain progress, ranging from epidemiological studies to molecular research, yet there are still deficiencies. In the future, large-scale population cohort studies and multidisciplinary integrated research need to be carried out to further explore the specific mechanisms. Meanwhile, these studies will contribute to the formulation of public health policies.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1877/rc

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1877/prf

Funding: This work was supported by the National Natural Science Foundation of China (grant No. 82460559), the Fundamental Research Funds for the Central Universities of Lanzhou University (No. lzujbky-2023-stlt01), Gansu Province Health Industry Science and Technology Innovation Major Projects (No. GSWSKY2024-06), the Cuiying Scientific and Technological Innovation Program of the Second Hospital of Lanzhou University (Nos. CY2022-YB-A04, CY2023-MS-B17, and CY2024-MS-B18) and Major Project of the Gansu Provincial Joint Research Fund: Investigation of High-Risk Environmental Factors Associated with Gastric Cancer and Development of Prevention and Treatment Technologies (No. 25JRRA1264).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1877/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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