Hidden in plain sight: a narrative review on environmental exposures and the fight against mesothelioma

Abstract

Background and Objective

Mesothelioma remains lethal, with a growing share linked to non-occupational exposure in community settings. This review synthesizes contemporary epidemiology, mechanisms, exposure sources, diagnosis, treatment and public health strategies.

Methods

This narrative review was conducted to synthesize heterogeneous evidence addressing environmental and para-occupational asbestos exposure and its relationship to malignant mesothelioma. A structured literature search was performed using PubMed/MEDLINE, Embase, and Web of Science databases for articles published through 2025. Terms related exclusively to occupational exposure were deliberately deprioritized. Studies were eligible for inclusion if they met at least one of the following criteria: (I) epidemiological investigations evaluating non-occupational, environmental, or para-occupational asbestos exposure; (II) mechanistic or toxicological studies elucidating fiber pathogenicity relevant to environmental exposure scenarios; (III) investigations of population clusters associated with naturally occurring or construction-related mineral fibers; (IV) studies assessing environmental remediation, surveillance strategies, or public-health interventions; or (V) clinical investigations reporting data stratified by exposure category. Articles focusing exclusively on occupational exposure without environmental relevance were excluded. Case reports without exposure characterization, editorials without primary data, and studies lacking clear methodological description were also excluded.

Key Content and Findings

Environmental risk arises from naturally occurring asbestos (NOA), legacy building materials, industrial residues and para-occupational transfer into homes. Case mix is shifting toward women, younger patients and peritoneal presentations in geologic or industrial hotspots. Fiber biopersistence drives chronic inflammation, oxidative injury and mesothelial transformation. Systemic therapy now centers on dual checkpoint blockade as a first-line standard, with chemo-immunotherapy and platinum-pemetrexed backbones, and selective use of bevacizumab. Surgery is reserved for candidates in expert centers, favoring lung-sparing pleurectomy and decortication when macroscopic clearance is plausible. Prevention requires total prohibition of new asbestos use, disciplined legacy management, robust enforcement, land-use controls in NOA terrains, and household protections.

Conclusions

Environmental drivers will sustain mesothelioma burden unless exposure pathways are eliminated and legacy sources are controlled. Clinical gains come from immunotherapy, selective surgery and coordinated supportive care, but prevention and earlier detection carry the greatest impact. A unified agenda that couples exposure science with equitable public health action is essential to bend incidence and improve outcomes.

Introduction

Malignant mesothelioma is an aggressive serosal cancer, predominantly pleural and driven by prior asbestos exposure in the majority of cases. Despite therapeutic advances, prognosis remains poor with survival typically measured in months, underscoring the primacy of prevention and early detection (1). Although long framed as the archetypal occupational malignancy, mesothelioma’s burden increasingly reflects exposures outside the workplace, dispersed through communities by legacy construction materials, naturally occurring mineral deposits, industrial emissions, and domestic para‑occupational pathways. These environmental risks tend to be chronic, low to moderate in rate of cumulative dose accrual, and frequently unrecognized. As such, these dangerous exposures are “hidden in plain sight”, shaping contemporary epidemiology while evading conventional surveillance.

Global patterns mirror historical asbestos consumption and the disease’s protracted latency (often 20–50 years). Incidence has plateaued or declined in countries that curtailed amphibole and chrysotile use decades ago. But this disease has persisted in older populations and in regions where asbestos continues to be mined, imported or embedded in the community’s environment. Annual deaths number in the tens of thousands worldwide (2). Age‑standardized rates vary by geography and fiber history, but the signal remains unmistakable. In environments in which fibers concentrate and are seen in high levels, such as shipyards and demolition corridors, mesothelioma follows. The result is a shifting case‑mix, with a growing proportion of diagnoses among women, neversmokers and residents lacking direct industrial contact, particularly in rural districts overlying ultramafic rock or in urban neighborhoods undergoing redevelopment (2).

Distinguishing environmental from occupational mesothelioma is not semantic but instead is etiologic and programmatic. Occupational exposure typically entails higher short-term contributions to cumulative dose in controlled settings, documented by job titles and exposure matrices. Environmental exposures, by contrast, involve sustained, lower‑dose cumulative fiber dose with diffuse sources and poorer documentation. Paraoccupational transmission through contaminated clothing and household dust further blurs categories, creating familial clusters decades after primary industries wane (3). Spatial epidemiology reveals micro‑hotspots around naturally occurring asbestos (NOA) outcrops, legacy vermiculite or cement plants, brake‑lining corridors, informal construction and waste sites and communities with fiber‑contaminated talc or other mineral coexposures (4). In such settings, the demographic signature shifts toward younger onset in some clusters, higher female representation and a greater share of peritoneal disease.

Mechanistically, environmental and occupational pathways converge on fiber biopersistence and mesothelial injury. Amphibole and chrysotile asbestos, erionite zeolites and region‑specific amphiboles (e.g., fluoro‑edenite) exhibit variable potency but common features such as high aspect ratio, durability, and reactive surfaces. Following inhalation or less commonly ingestion, fibers translocate to the pleura or peritoneum, where frustrated phagocytosis, iron‑catalyzed redox cycling and chronic sterile inflammation sustain mesothelial damage. Danger signaling [e.g., high mobility group box 1 (HMGB1) release], inflammasome activation and cytokine milieus foster genomic instability and immune evasion. The mesothelioma genome, characterized by recurrent loss‑offunction events in tumor suppressors such as breast cancer gene 1-associated protein 1 (BAP1), neurofibromatosis type 2 (NF2) (Hippo pathway) and cyclin-dependent kinase inhibitor 2A (CDKN2A), interacts with exposure biology. The germline BAP1 alterations amplify susceptibility at relatively low cumulative doses, converting environmental cumulative fiber dose into penetrant cancer risk within families and small communities (5-7). Epigenetic remodeling and chromothripsislike structural changes further embed exposure history into malignant phenotype. Throughout this review, the magnitude of asbestos exposure is described using the unifying parameter cumulative dose, defined as the integrated burden of respirable fibers accrued over time. This construct accommodates variability in exposure scenarios, including short-duration high rate of cumulative dose accrual occupational exposures and low-rate, long-duration cumulative dose accrual environmental or para-occupational exposures, while providing a consistent framework for epidemiologic comparison and risk interpretation.

Weathering of asbestos-containing materials (ACMs) during routine renovation, traffic-generated resuspension of roadbed serpentine, wind-borne dispersal from NOA cut-and-fill activities and the secondary transport of fibers on clothing and furnishings maintain ambient concentrations sufficient for risk in susceptible populations. Disaster-related building collapse and unregulated informal recycling can generate intense, short-term plumes whose mesothelioma impact will manifest only after decades. The absence of a known safe threshold, the long latency and the difficulty of individual dose reconstruction complicate attribution, litigation, and policy. But these factors also demand a shift from after-the-fact compensation to forward-leaning primary prevention and community-level risk management.

This review has four objectives. Firstly, we will synthesize contemporary epidemiology of mesothelioma with an emphasis on environmental, para‑occupational, and geogenic exposures. Secondly, we will integrate pathophysiologic and mechanistic data linking low‑dose, chronic fiber exposure to carcinogenesis, including inflammatory, genetic, epigenetic axes and the role of inherited susceptibility. Thirdly, we will catalogue and critically appraise environmental sources, including NOA, household contamination, industrial pollution, emergent non‑asbestos fibrous carcinogens, exposure assessment tools, biomarkers and imaging approaches suited to community settings. Finally, we will evaluate current treatment strategies in the specific context of environmentally exposed populations We will evaluate public‑health interventions, regulation and enforcement, remediation and land‑use planning, exposure‑informed screening, early detection and equitable surveillance frameworks that capture at‑risk communities rather than only insured workers. By reframing mesothelioma as both an occupational risk and an issue related to environmental injustice, we aim to translate mechanistic insight and spatial epidemiology into actionable prevention. Identifying and interrupting environmental fiber pathways before malignant transformation remains the most powerful strategy to utilize. We present this article in accordance with the Narrative Review reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-aw-2134/rc).

Methods

A structured literature search was performed using PubMed/MEDLINE, Embase, and Web of Science databases for articles published through 2025. Additional sources were identified through manual review of reference lists from key reviews, consensus statements, and population-based reports. Search terms included combinations of: mesothelioma, environmental exposure, non-occupational exposure, para-occupational exposure, naturally occurring asbestos, erionite, fluoro-edenite, vermiculite, fiber pathogenicity, asbestos remediation, public health surveillance, geospatial analysis, and environmental clusters. Terms related exclusively to occupational exposure were deliberately deprioritized unless the study provided relevant comparative or contextual data. Additional information regarding search criteria are shown in Table 1.

Table 1. Criteria used for literature review.

Criteria used in methodological search

Epidemiologic studies examining environmental or para-occupational asbestos exposure outside traditional workplace settings

Experimental, mechanistic, or toxicological investigations elucidating fiber pathogenicity and carcinogenic mechanisms relevant to low-dose or chronic exposure

Studies describing disease clusters linked to naturally occurring asbestos or asbestos-like mineral fibers in residential or community settings

Research evaluating environmental remediation strategies, exposure surveillance systems, geospatial analyses, or population-level public-health interventions

Clinical investigations reporting outcomes or disease characteristics stratified by exposure source (environmental, para-occupational, or mixed exposure)

Population-based registries, spatial epidemiology studies, or cohort analyses incorporating residential history or geographic exposure assessment

Policy, regulatory, or implementation studies addressing asbestos management, building materials, or infrastructure-related exposure prevention

Epidemiologic studies examining environmental or para-occupational asbestos exposure outside traditional workplace settings

Experimental, mechanistic, or toxicological investigations elucidating fiber pathogenicity and carcinogenic mechanisms relevant to low-dose or chronic exposure

Studies describing disease clusters linked to naturally occurring asbestos or asbestos-like mineral fibers in residential or community settings

Studies were eligible for inclusion if they met at least one of the following criteria: (I) epidemiological investigations evaluating non-occupational, environmental, or para-occupational asbestos exposure; (II) mechanistic or toxicological studies elucidating fiber pathogenicity relevant to environmental exposure scenarios; (III) investigations of population clusters associated with naturally occurring or construction-related mineral fibers; (IV) studies assessing environmental remediation, surveillance strategies, or public-health interventions; or (V) clinical investigations reporting data stratified by exposure category.

Articles focusing exclusively on occupational exposure without environmental relevance were excluded. Case reports without exposure characterization, editorials without primary data, and studies lacking clear methodological description were also excluded. Titles and abstracts were screened for relevance, followed by full-text review of eligible articles. Evidence was synthesized qualitatively, with emphasis on consistency across epidemiologic, mechanistic, clinical, and public-health domains rather than formal meta-analysis, given substantial heterogeneity in exposure definitions and outcome measures. The strength and limitations of available evidence were considered narratively, with priority given to population-based studies, well-characterized exposure assessments, and multidisciplinary investigations. The overall search strategy summary is shown in Table 2.

Table 2. The search strategy summary.

Items	Specification
Date of search	October 17, 2025
Databases searched	PubMed/MEDLINE, Embase, and Web of Science
Search terms used	Mesothelioma, environmental exposure, non-occupational exposure, para-occupational exposure, naturally occurring asbestos, erionite, fluoro-edenite, vermiculite, fiber pathogenicity, asbestos remediation, public health surveillance, geospatial analysis, and environmental clusters
Timeframe	January 1960—December 2025
Inclusion criteria	Epidemiological investigations, mechanistic or toxicological studies, investigations of population clusters, studies assessing environmental remediation and clinical investigations written in English or with English translation available
Selection process	The three authors conducted the search and selection process, including only studies that reached consensus agreement among all authors

Sources of environmental exposure

Environmental exposure to asbestos and related fibrous minerals arises from diverse, often unrecognized pathways. These exposures differ from traditional occupational contact in their diffuse nature, lower rate of cumulative dose accrual, and extended duration. The sources can be broadly categorized into naturally occurring deposits, household contamination, industrial pollution and emerging non-asbestos carcinogens (8).

NOA refers to fibrous minerals embedded within ultramafic and serpentine rock formations. Weathering and human disturbance of these deposits release fibers into ambient air and soil (9). Road construction, mining, and residential development on asbestos-bearing land amplify dispersal. Inhalation of fibers from road dust or wind-borne particles has been linked to mesothelioma clusters in rural areas such as Cappadocia in Turkey and regions of the western United States (10). Similar risks persist in Italy, Greece, and China where geologic deposits intersect with populated areas (11). The challenge lies in the silent nature of exposure, as residents are often unaware of the mineralogical risk beneath their communities (12).

Para-occupational or secondary exposures arise when workers transport asbestos fibers into domestic environments not only on clothing and footwear, but also on hair and skin, or through asbestos-containing materials and waste products brought home from work for secondary use (13). Once interior household surfaces became contaminated, routine activities such as sweeping floors, dusting furniture, or laundering work clothes generated unexpectedly high concentrations of respirable fibers, substantially increasing cumulative dose among household members, including children (14,15).

Legacy asbestos use in urban infrastructure contributes significantly to environmental exposure. ACMs in schools, public housing, and commercial buildings degrade over time. Renovation, demolition, and natural disasters such as earthquakes or building collapses can release concentrated fiber plumes (16). Industrial activities including shipbuilding, cement production and brake manufacturing have left persistent environmental reservoirs. Communities adjacent to such facilities often show higher mesothelioma incidence even without direct workplace contact. Airborne fibers may travel considerable distances, creating exposure gradients across neighborhoods. Waste disposal sites containing asbestos debris further compound risk when regulations are absent or poorly enforced.

Beyond asbestos, several fibrous silicates and synthetic materials exhibit mesothelioma-inducing potential (17). Erionite, a zeolite mineral with high carcinogenicity, has caused devastating mesothelioma epidemics in Cappadocia and parts of North America. Fluoro-edenite, a fibrous amphibole present in volcanic ash near Biancavilla, Sicily, has similarly been implicated in localized mesothelioma clusters. Concerns also extend to man-made mineral fibers, carbon nanotubes and other engineered nanomaterials that share physical properties with asbestos, including high aspect ratio and biopersistence (18). While human evidence remains limited for these newer agents, their mechanistic similarity to asbestos warrants vigilance and preventive oversight.

The environmental sources of mesothelioma are broad, multifactorial, and frequently underrecognized (19). Natural deposits, domestic contamination, urban decay and novel fibrous materials all contribute to an enduring public health burden. Unlike occupational exposures, which can often be traced to specific industries, environmental exposures arise diffusely and can affect entire communities. Recognizing and cataloging these sources is critical for prevention, risk assessment and policy development aimed at reducing mesothelioma incidence in the coming decades (20).

Clinical presentation and diagnosis

Cases of mesothelioma that arise from environmental exposures demonstrate a clinical presentation that is largely indistinguishable from cases related to occupational exposure. Patients typically develop symptoms such as progressive dyspnea, non-pleuritic chest pain and chronic cough, with additional constitutional symptoms such as fatigue and unintended weight loss. These symptoms are often secondary to a malignant pleural effusion or mass effect by the tumor itself (21,22). Although presentations can be similar, patients with environmental causes of mesothelioma can present at a younger age and exhibit a more balanced gender distribution with an almost one to one male-to-female ratio, in contrast to the male predominance typically observed in cases related to occupational exposure (23).

The initial diagnostic evaluation typically begins with chest radiography and contrast-enhanced computed tomography (CT), which may demonstrate pleural thickening, effusion or discrete pleural-based masses. CT findings that raise suspicion for malignancy include circumferential pleural rinds, nodular pleural thickening and mediastinal involvement. Magnetic resonance imaging (MRI) provides superior delineation of local invasion, particularly into the chest wall, diaphragm or mediastinum, while positron emission tomography computed tomography (PET-CT) offers an assessment of metabolic activity and aids in staging. However, PET-CT must be interpreted with caution, as inflammatory processes can result in false-positive findings. Serologic biomarkers such as soluble mesothelin-related peptide and osteopontin have demonstrated limited diagnostic accuracy and are not recommended for routine use in establishing a diagnosis (24). Histopathological confirmation via pleural biopsy remains the diagnostic gold standard. When obtaining a biopsy, it is important to obtain a full-thickness biopsy to allow the pathologist to make an accurate diagnosis. Immunohistochemical panels incorporating mesothelial markers such as calretinin, cytokeratin 5/6, Wilms’ tumor 1 (WT1) and podoplanin (D2-40) are essential for confirming mesothelioma and differentiating it from metastatic adenocarcinoma. In addition, loss of breast cancer gene 1 (BRCA1)-BAP1 nuclear expression has emerged as a valuable ancillary marker, particularly in distinguishing malignant mesothelioma from reactive mesothelial proliferations.

Distinguishing environmental from occupational mesothelioma can be challenging, as the clinical manifestations are often indistinguishable. A detailed exposure history, consideration of geographic clustering and recognition of demographic patterns are essential. Environmental cases more frequently present in younger individuals and in females, particularly among populations residing near NOA deposits or in areas with industrial contamination. By contrast, occupational cases predominate in older males with a history of employment in high-risk industries such as construction, shipbuilding and manufacturing (25).

Discussion

Epidemiology of mesothelioma in the context of environmental exposure

Malignant mesothelioma remains a paradigmatic latency-driven malignancy, with incidence patterns reflecting historical asbestos consumption, demographic transitions, and the slow accrual of risk from environmental exposure (26). While occupational exposure dominated case ascertainment throughout much of the twentieth century, contemporary epidemiology increasingly reflects population-level exposure occurring outside formal workplaces, including residential proximity to asbestos-contaminated sites, NOA, and para-occupational transfer (27,28).

The prolonged latency period—often exceeding 30–50 years—necessitates population-based mesothelioma registries as essential epidemiologic instruments (29,30). Robust registries enable: (I) identification of occupational, para-occupational, and environmental exposure pathways; (II) early detection of temporal and spatial clusters; (III) attribution of asbestos dispersion beyond industrial boundaries; and (IV) facilitation of timely diagnosis, access to expert care, and eligibility for compensation (31). National registry systems, particularly in Italy and France, have demonstrated the value of registry-driven surveillance in detecting community clusters adjacent to former asbestos-cement plants, shipyards, and contaminated waste sites.

Given demographic shifts toward women, younger patients, and a higher proportion of peritoneal disease—particularly in environmentally exposed cohorts—registry data must incorporate residential history, household contact exposure, and geospatial variables (32,33). Without such integration, environmentally mediated disease remains systematically under-ascertained.

Long-term national strategies for asbestos-contaminated sites are therefore indispensable (34,35). These strategies must include systematic site identification, risk stratification, remediation planning, and transparent risk communication (36-38). In parallel, analytical epidemiologic studies—particularly cohort and case-control designs in areas with documented or suspected contamination—are critical for quantifying low-dose risk (39). Increasingly, GIS-based spatial analysis has emerged as a key tool for identifying at-risk communities and correlating disease incidence with geological substrates, land-use practices, and legacy industrial activity.

Environmental and para-occupational exposure pathways

Environmental exposure to asbestos fibers arises through territorial contamination, defined as the dispersion of asbestos fibers into the outdoor environment beyond the industrial site of origin (40). Such contamination reflects historical industrial practices lacking dust-abatement measures, abandonment of friable asbestos-containing waste, and secondary use of asbestos materials in construction and land fill (41).

Para-occupational exposure represents a major and often under-recognized pathway, whereby fibers transported on clothing, footwear, and equipment introduce asbestos into domestic environments (29). Epidemiologic studies consistently demonstrate elevated mesothelioma risk among spouses and children of asbestos workers, frequently decades after cessation of industrial activity.

Unlike occupational exposure—which is often temporally bounded and documented—environmental and para-occupational exposures are diffuse, chronic, and poorly captured by conventional exposure matrices (42). This distinction has significant implications for both epidemiologic surveillance and clinical risk attribution.

Geological and mineralogical risk factors

NOA and asbestos-like fibrous minerals represent major environmental determinants of mesothelioma risk. Ultramafic and serpentine rock formations release fibers through weathering, construction, mining, and land disturbance (26-28). Minerals implicated in mesothelioma clusters—such as fluoro-edenite in Biancavilla, vermiculite in Libby, Montana, and erionite in parts of Turkey—were not solely sources of passive environmental exposure. These materials were extensively processed and deliberately incorporated into local construction practices, including building materials, road aggregate, insulation, and infrastructure. Consequently, a substantial proportion of mesothelioma cases in these regions are attributable to occupational and para-occupational exposures arising from the handling, processing, and manipulation of these minerals during construction and maintenance activities, rather than from ambient environmental exposure alone (43,44).

Mineralogical characterization is therefore central to environmental risk assessment (45). Fiber dimension, durability, and surface chemistry—rather than asbestos classification alone—determine carcinogenic potential (46). Failure to integrate geological mapping into land-use planning perpetuates preventable community exposure (47).

Susceptibility and gene–environment interaction

Environmental exposure alone does not fully account for mesothelioma risk. Germline susceptibility—most notably BAP1 tumor predisposition syndrome—dramatically lowers the exposure threshold required for carcinogenesis (48). In such individuals, modest environmental cumulative fiber dose translate into high lifetime risk, often with earlier onset, peritoneal involvement, and familial clustering (49).

These observations firmly establish mesothelioma as a gene–environment disease, with direct implications for surveillance prioritization, genetic counseling, and ethical risk communication in environmentally exposed communities.

Epidemiology of low-dose environmental exposure

No safe threshold for asbestos exposure has been established (50). Epidemiologic studies increasingly demonstrate measurable mesothelioma risk at fiber concentrations far below those encountered occupationally (51). Low-dose exposure predominates in community settings yet remains the least precisely quantified exposure category.

Standardized metrics for environmental exposure are lacking, with heterogeneous methodologies encompassing air sampling, soil analysis, lung cumulative fiber dose, and residential proximity models (52). This variability complicates cross-study comparison and policy translation, reinforcing the need for harmonized exposure definitions and prospective monitoring frameworks (53).

Clinical implications for environmentally exposed populations

Clinical presentation does not reliably distinguish environmental from occupational mesothelioma. However, environmental exposure shapes clinical decision-making through delayed recognition, diagnostic latency, and barriers to referral. Patients without occupational history are less likely to trigger early diagnostic suspicion, contributing to advanced-stage presentation at diagnosis.

From a public-health perspective, clinicians function as sentinel detectors of environmental risk. Persistent unilateral pleural effusion, peritoneal disease in women, or geographic clustering should prompt detailed exposure assessment and public-health notification.

Public-health strategies and surveillance models

Effective prevention requires integration across exposure science, clinical medicine, and public policy (54). Priority strategies include:

• ❖ Population-based mesothelioma registries with geocoded exposure data;

• ❖ Geographic information system (GIS)-driven identification of environmental hotspots;

• ❖ Risk-stratified surveillance for residents of contaminated areas, para-occupational contacts, and germline BAP1 carriers;

• ❖ Standardized environmental monitoring and rapid remediation pathways;

• ❖ Treatment strategies for patients diagnosed with disease (55-59).

The risk associated with asbestos-containing materials varies substantially according to their physical state: compact (non-friable) materials, such as intact asbestos-cement panels or vinyl tiles, generally pose limited risk when undisturbed, whereas friable materials—such as sprayed insulation, deteriorating pipe lagging, or damaged ceiling panels—readily release fibers and represent a significantly higher hazard. Aging schools and public housing disproportionately contain friable materials, underscoring the need for prioritized inspection, maintenance, and remediation.

Current gaps in environmental monitoring—particularly in rural and socioeconomically disadvantaged communities—delay detection and intervention. Equitable surveillance requires sustained funding, transparent governance, and community engagement.

Patients exposed to low environmental doses face complex decision-making, characterized by uncertainty regarding individual risk, latency, and benefit of surveillance. Clear communication shared decision-making frameworks, and linkage to remediation resources are essential.

Limitations

This narrative review has several limitations. Environmental exposure data are frequently incomplete, heterogeneous, and retrospective. Definitions of low-dose exposure vary widely, and standardized quantitative thresholds are lacking. Distinguishing occupational from environmental exposure is often constrained by recall bias and incomplete work histories. Additionally, environmental monitoring infrastructure remains uneven across regions, limiting generalizability. These limitations underscore the need for prospective, standardized, interdisciplinary research frameworks.

Future directions and research gaps

One critical future direction is refining how environmental asbestos exposure is measured and monitored. Traditional occupational exposure metrics do not capture the low-dose, chronic exposures that occur in community settings. There is a pressing need for more granular exposure for example assessment tools, including detailed residential histories, geospatial mapping of asbestos hotspots and advanced sensor technologies for environmental fiber detection. Open questions remain about what constitutes a ‘hazardous’ environmental dose; the World Health Organization (WHO) emphasizes that even very low ambient airborne asbestos concentrations contribute to cumulative dose and are associated with increased risk of asbestos-related diseases, including mesothelioma, particularly with long-term exposure (WHO Air Quality Guidelines). Clarifying these dose-response relationships at low levels will require multidisciplinary research. One approach has been to analyze asbestos cumulative fiber dose in lung tissue from exposed individuals, which in one United Kingdom (U.K.) study enabled quantification of mesothelioma risk (approximately 0.02% per 1,000 retained amphibole fibers per gram of lung). However, obtaining such data is challenging due to the rarity of autopsies and legal hurdles in accessing tissue. Future studies must therefore innovate noninvasive or community-based exposure indicators—for instance, environmental sampling, biomonitoring, or novel biomarkers of cumulative fiber dose—to better identify at-risk populations. Research should also extend to emerging fiber hazards beyond asbestos, such as naturally occurring mineral fibers and high-aspect-ratio nanomaterials, ensuring that their carcinogenic potential is understood and factored into prevention strategies. In tandem with improved exposure assessment, accurate case identification remains paramount. This means investing in precise diagnostic practices (e.g., expert pathology review and adequate biopsy sampling) so that mesothelioma cases, especially those in non-occupational settings, are correctly diagnosed and linked to possible environmental causes. Strengthening exposure assessment will ultimately inform better policy and public health interventions by defining the true scope of environmental risk.

Another area is in the molecular and genetic domain. Scientists are working to unravel the genetic predispositions and mechanistic pathways that modulate mesothelioma development in environmentally exposed individuals. A high priority is to identify additional susceptibility genes beyond the well-known BAP1 mutation syndrome. It appears likely that, in addition to BAP1, other inherited variants contribute to mesothelioma risk—especially among those with lower-level asbestos exposure. Large-scale genomic studies and family-based investigations are needed to pinpoint these risk-modifying genes. Parallel efforts are probing the biological “fingerprints” that asbestos and related fibers leave on cells. Inhaled fibers can trigger chronic inflammation and DNA damage; for example, they induce release of HMGB1 and other mediators that drive mesothelial injury. Such insights have opened the door to biomarker research. At present, there is no validated blood marker for early mesothelioma detection in exposed populations, but candidates are emerging. HMGB1 and fibulin-3, for instance, have shown promise as potential biomarkers that are elevated in asbestos-exposed individuals (and further elevated in mesothelioma patients). Future studies will need to validate these and other biomarkers in large cohorts, assessing whether they can reliably distinguish early malignancy from benign effects of exposure. This requires multicenter collaboration and biobank initiatives to gather enough high-risk individuals for analysis (60,61).

Beyond protein markers, newer “omics” approaches are being applied to mesothelioma research. Epigenetic profiling has revealed distinct DNA methylation signatures in mesothelioma tissues that correlate with asbestos cumulative fiber dose and clinical outcomes. Such exposure-linked epigenetic changes could not only improve our understanding of pathogenesis but also suggest targets for therapy or prevention. Transcriptomic and proteomic studies may likewise uncover early molecular changes in mesothelial cells after chronic fiber exposure. By integrating genomics, epigenomics and advanced in vitro models, researchers aim to build a detailed picture of how environmental carcinogens cause mesothelioma at the molecular level. This knowledge will inform both risk assessment (for example, identifying gene-environment interactions that amplify risk) and the development of targeted interventions to interrupt disease processes before malignancy occurs.

There is considerable interest in translating these advances into novel therapeutic interventions for mesothelioma. Despite some progress, current treatment outcomes remain unsatisfactory for most patients, which underscores the need for innovative therapies. Immune checkpoint inhibitors have recently become part of the standard of care and can prolong survival, but the majority of mesothelioma patients fail to achieve durable benefit or eventually develop resistance to immunotherapy. To address this, researchers are exploring combination strategies to enhance efficacy. One promising approach is to combine immunotherapy with epigenetic therapy—drugs that modulate DNA methylation or histone acetylation—as a means to “reprogram” tumor cells and the immune microenvironment to be more responsive to checkpoints. Early studies suggest that epigenetic agents can upregulate antigen presentation and reduce immunosuppressive signals in mesothelioma cells, thereby potentially overcoming some mechanisms of immunotherapy resistance (62). Clinical trials are now testing combinations of checkpoint inhibitors with deoxyribose nucleic acid (DNA)-demethylating agents or histone deacetylase inhibitors in mesothelioma, reflecting this strategy. Beyond immunotherapy, personalized medicine is a key frontier. Comprehensive genomic analyses of mesothelioma tumors have identified recurrent alterations (in tumor suppressors like NF2, CDKN2A and others), and these data are being leveraged to find new drug targets. For example, the frequent loss of BAP1 function has spurred interest in therapies targeting the epigenetic vulnerabilities of BAP1-deficient tumors [such as enhancer of Zeste homolog 2 (EZH2) inhibitors], and early-phase trials are investigating these agents. Similarly, inhibition of the FAK signaling pathway (implicated secondary to NF2 loss) has been explored, though with mixed results so far. The overarching idea is that mapping the mesothelioma genome will reveal tumor-specific weaknesses that next-generation drugs or drug combinations can exploit.

Researchers are also advancing entirely new therapeutic modalities. One cutting-edge area is adoptive cell therapy: chimeric antigen receptor (CAR) T-cells directed against mesothelioma-associated antigens (like mesothelin) have entered early clinical trials. Preliminary reports indicate that mesothelin-targeted CAR T-cells can be administered safely and show signs of anti-tumor activity in mesothelioma, validating the concept that such immune-engineered cells have in vivo efficacy (61). Ongoing studies are refining CAR T-cell designs to improve their tumor selectivity and persistence, including regional (pleural) delivery to mitigate off-tumor effects. Other immunotherapeutic approaches under investigation include tumor vaccines (aimed at provoking an immune response to mesothelioma-specific antigens) and oncolytic viruses engineered to infect and kill mesothelioma cells while stimulating immunity. Each of these novel strategies addresses different aspects of the cancer’s resistance to treatment. It is expected that, over the next decade, the care of mesothelioma will increasingly incorporate such targeted and immune-based therapies alongside traditional surgery, chemotherapy and radiation. However, bringing these innovations from bench to bedside will require continued clinical trials and research investment.

Conclusions

Mesothelioma remains a lethal cancer with growing environmental drivers. Low level chronic exposures cause disease after long latency. Case mix is shifting toward women and non workers. Mechanisms mirror occupational pathways with persistent inflammation and genomic injury. Current care favors immunotherapy, selective surgery and supportive radiotherapy. Chemotherapy remains a backbone. Prevention and earlier detection therefore remain decisive.

Beyond regulatory bans, effective remediation and the safe removal of asbestos-containing materials are central to preventing population exposure. Proper management of asbestos embedded in buildings, schools, housing stock, and infrastructure—particularly the identification and controlled removal of friable materials—represents one of the most impactful public-health interventions to reduce cumulative dose at the community level. Sustained investment in remediation programs, enforcement of abatement standards, and transparent risk communication are therefore essential to preventing future mesothelioma and other asbestos-related diseases.

Research should quantify low dose exposure with modern sensors and geospatial methods. Validate early detection biomarkers in large well phenotyped cohorts. Define genetic susceptibility beyond BAP1 to enable targeted screening. Advance immunotherapy combinations and rational targeted agents. Prioritize pragmatic trials that reflect environmental case mix.

Supplementary

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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.