Beyond Classic Carcinogens: Micro- and Nanoplastics (MNPs) as Pervasive Factors in Cancer Risk

Abstract

Cancer is attributed to being caused by multiple genetic, epigenetic, and various direct and indirect environmental factors. Microplastics are defined as pieces of plastic that are smaller than five millimeters. Microplastics have been emphasized as ubiquitous environmental contaminants found in terrestrial and aquatic systems, food webs, and the human body. Moreover, microplastics can bind to environmentally harmful pollutants, heavy metals, and refractory organic pollutants that can aggravate the biological effects of these pollutants. Microplastics are suggested to induce chronic inflammation, oxidative stress, and genotoxicity by adsorbing and modifying the biomolecules in the biological systems. Oxidative stress, inflammation, and chemical-induced genetic and epigenetic changes in cancer cells and cancer-associated cells are considered as crucial processes in the development, progression, and therapeutic outcome of cancer. Among numerous tumor-promoting environmental factors, preclinical and clinical evaluations of how microplastics contribute to cellular and non-cellular pro-tumorigenic mechanisms like inflammation, genomic instability, and epigenetic modulation are emerging. This review will contribute to a better understanding of microplastics as additional environmental components apart from established carcinogens and genotoxic substances that directly or indirectly influence the pro-tumor microenvironment.

1. Introduction

Cancer is a multifaceted condition driven by several factors, including uncontrolled cell growth, resistance to programmed cell death, and the ability to metastasize to distant body sites [1,2,3,4,5]. Its development stems from a complex interplay of biological factors, including genetic mutations and epigenetic alterations, and environmental components, including anthropogenic pollutants. These cellular and non-cellular components together influence tumor development, progression, and the outcomes of therapeutic interventions [6,7,8,9,10,11].

Additionally, various forms of chemicals emanating from the environment, including those from tobacco smoke, air pollutants, and some food components, contribute to modifying epigenetic marks and thus promoting carcinogenesis [10,11,12,13].

Micro- and nanoplastics (MNPs) are tiny synthetic polymer fragments that are now ubiquitous across ecosystems, including freshwater, marine environments, soils, sediments, air, drinking water, and food [14,15,16,17,18]. They are increasingly recognized as significant anthropogenic particulate pollutants. MNPs arise from primary sources (manufactured micro/nanoplastics) and secondary sources (degradation of larger plastics). Physical, chemical, and biological weathering progressively convert macroplastics into microplastics and ultimately into nanoplastics [13,19,20].

Recent studies have detected MNPs in human tissues, including tumors [13,19,20,21,22,23]. Within the body, these particles can provoke inflammation, oxidative stress, genetic alterations, and immune disruption, all of which are implicated in various human diseases, including cancer [15,21,24,25,26,27,28,29,30,31,32,33,34,35]. Their strong surface reactivity also enables them to adsorb and transport carcinogenic contaminants such as PAHs, heavy metals, and persistent organic pollutants, amplifying their malignant potential [19,23,36,37].

Humans are exposed to MNPs through ingestion, inhalation, and dermal contact. After entry, they can accumulate in organs such as the lungs and gastrointestinal tract, causing cellular dysfunction, DNA damage, and chronic inflammation [14,15,17,18,20,38,39,40]. These disruptions can alter the tumor microenvironment (TME) by promoting tissue injury, immune imbalance, and mutagenesis [9,12,41].

In the proposed paper, most of the existing evidence linking MNP exposure to human cancers is associative rather than causal. In addition to in vitro and preclinical studies, human studies are limited. Direct and quantitative data on bioaccumulation thresholds of MNP exposure that can trigger pathophysiological carcinogenic alterations in humans remain underexplored. This review evaluates and discusses the various forms of available evidence, including cellular, preclinical, and clinical, linking microplastics to cancer, and it also identifies methodological and conceptual gaps, and proposes research frameworks for future studies.

2. Emerging Multifaceted Origins of Cancer

Cancer is known to arise from a complex interplay of genetic, environmental, and socio-economic factors. Tumor attributes encompass disruption of cellular homeostasis, leading to uncontrolled growth, immune evasion, and metastasis [42,43,44]. Central to this process is the TME, a dynamic niche of stromal cells, immune cells, the extracellular matrix (ECM), and vasculature. The TME is not merely a backdrop but an active participant; continuous crosstalk between cancer cells and their surroundings drives tumor initiation and progression [1,2,4,5,9,41,43,45,46].

2.1. Genetic and Epigenetic Factors

The transition from healthy to cancer is primarily fueled by the overactivation of oncogenes (unregulated proliferation) and the inactivation of tumor suppressor genes like TP53 and BRCA1 (loss of cell cycle control) [7,47]. Regarding epigenetic alterations, DNA methylation and histone modifications can silence protective genes without altering the underlying DNA sequence [46,48,49]. These changes are often triggered by chronic inflammation, dietary factors, and exposure to carcinogens [46].

2.2. The Role of the Microenvironment (TME)

Cancer cells actively remodel the TME to facilitate survival. Hypoxia within the tumor promotes genetic instability and angiogenesis, while the ECM is reorganized to support migration [46,50]. Furthermore, chronic inflammation induced by infection or environmental triggers supports pro-tumorigenic environment by damaging DNA and suppressing anti-tumor immunity [46,50].

2.3. Environmental and Biological Exposures

Global cancer burdens are significantly influenced by external physical and chemical forms of carcinogens such as UV radiation, tobacco smoke (the primary driver of lung cancer), asbestos, and pollutants, which are established mutagens and carcinogens [45,51,52]. Furthermore, biological pathogenic agents such as HPV, HBV, and Helicobactor pylori are known to induce malignancy by integrating into host genomes or causing persistent tissue damage [6]. Besides several sources of direct and indirect forms of physical, chemical, and biological agents acting as cancer initiators and promoters, environmental agents are also emerging. These agents such as MNPs, are being considered as rising contaminants, and that could be additive and indirect potentiators of known physical, chemical, and biological carcinogens [31,32,33,34,35,53]. These MNPs are suggested to trigger oxidative stress, act as endocrine disruptors, or carry hazardous chemicals like bisphenol A, potentially impairing genomic stability [31,54,55]. However, direct evidence that can link the role of MNPs as mutagens and carcinogens is limited [31,32,54,55]. A summary of environmental exposures and cancer development is illustrated in Figure 1.

2.4. Lifestyle and Socio-Economic Factors

Individual risk is further compounded by lifestyle behaviors, including obesity, sedentary habits, and alcohol use [6,56]. However, these risks are often shaped by socio-economic disparities. Lower socio-economic status frequently correlates with higher exposure to environmental pollutants, limited healthcare access, and cultural practices, such as betel nut chewing, that increase specific cancer risks [56]. In summary, while traditional carcinogens (e.g., PAHs, asbestos) are well-documented, a significant gap remains in understanding the synergistic effects of emerging contaminants like MNPs. Developing standardized exposure models is essential for sustainable environmental policy and the creation of targeted public health interventions [34].

3. What Are the Sources and Types of Microplastics?

Anthropogenic industrial and consumer products are identified as major sources of microplastics, particularly microbeads. Such microbeads are commonly used in personal care items such as exfoliants, toothpaste, and facial cleansers [57,58,59]. In addition, synthetic textiles (e.g., polyester and nylon) continuously shed microscopic fibers during laundering. These generated microscopic fibers are suggested to pass through wastewater systems and ultimately reach aquatic environments [60]. Tire abrasion represents another significant contributor, as the mechanical breakdown of synthetic rubber generates fine plastic particles that are transported via road runoff into drainage networks [61]. Furthermore, large plastic debris undergoes progressive fragmentation under the influence of ultraviolet radiation, wave action, and microbial processes, yielding smaller plastic particles that persist in the environment [57].

Agricultural activities further intensify plastic contamination through the use of plastic mulch films, fertilizer coatings, and irrigation with treated wastewater. Such activities lead to the accumulation of plastic particles in soils and groundwater [62]. Collectively, these diverse and diffuse sources underscore the ubiquity of plastic pollution and the challenges associated with its management. Based on origin, plastics in the environment are broadly classified as primary and secondary microplastics [63]. Primary microplastics are intentionally manufactured at microscopic dimensions for specific applications. Conversely, secondary microplastics arise from the environmental degradation of larger plastic items. Inefficient waste management practices substantially accelerate the formation and dissemination of secondary microplastics. Consequently, microplastics are now detected across nearly all ecosystems, including oceans, seaweed, freshwater bodies, terrestrial soils, remote mountain regions, and polar ice [57,58,59]. A summary of types of microplastics, their compositions, and mechanisms of carcinogenicity is presented in

Table 1. Types of microplastics, their exposure routes, mechanisms of carcinogenicity and their chemical compositions.

Type of Microplastics	Exposure Routes	Mechanisms of Carcinogenicity	Chemical Composition	References
Microbeads	Cosmetics, personal care products, wastewater	Physical damage, inflammation, oxidative stress	Polyethylene (PE), polypropylene (PP), polyvinyl chloride (PVC)	[64]
Microfibers	Synthetic clothing, laundry wastewater	Inflammation, oxidative stress, DNA damage	Polyester (PET), nylon (PA), acrylic (PAN)	[65]
Microfragments	Plastic debris, food packaging	Physical damage, chemical leaching	Polyethylene terephthalate (PET), high-density polyethylene (HDPE)	[57]
Microplastic Additives	Food, water, consumer products	Endocrine disruption, chemical carcinogenesis	Phthalates, bisphenol A (BPA), organophosphates	[19]
Microplastic Films	Food packaging, agriculture	Physical damage, chemical leaching	Low-density polyethylene (LDPE), polyvinyl chloride (PVC)	[62]
Microplastic Spheres	Cosmetics, personal care products	Physical damage, inflammation	Polyethylene (PE), polypropylene (PP)	[66,67]
Nanoplastics	Food, water, air	Cellular uptake, oxidative stress, epigenetic changes	Polyethylene (PE), polyvinyl chloride (PVC), polystyrene (PS)	[68,69]

. Various sources of microplastics are depicted in Figure 2.

For clarity within the framework of this study, microplastics are defined as plastic particles typically ranging from ~1 µm to 5 mm. Whole nanoplastics represent the smaller fraction (<1 µm), often extending into the nanoscale (<100–1000 nm depending on definitions) [57,58,59]. Although both share common polymeric origins, nanoplastics differ fundamentally from microplastics in their higher surface-area-to-volume ratio, increased reactivity, enhanced cellular uptake, and greater potential to cross biological barriers. These properties may confer distinct biological behaviors and toxicological profiles, particularly within the TME.

In vitro and in vivo data on microplastics and cancer remain inconsistent. Identifying specific sources is difficult because biological samples vary widely in surface chemistry, size, and molecular properties. There are limitations of well-accepted analytical methods that can be employed for the classification system for size, morphology, and chemical composition of microplastics for deriving consistent findings. Additional factors, such as chemical aging, environmental weathering, and degradation, are not taken into consideration, which can mimic the real-world samples besides synthetic or laboratory-prepared sources of microplastics.

4. Uptake and Internalization of MNPs

MNPs smaller than 5 mm pose significant environmental and health risks due to their ability to be internalized by cells [70,71]. Understanding these entry mechanisms is vital for assessing subsequent biological impacts [71]. As illustrated in Figure 3, the pathways for cellular entry are highly dependent on the physical dimensions and surface properties of the particles.

4.1. Primary Pathways of Entry

The entry of MPs is primarily governed by phagocytosis and endocytosis [72,73,74,75,76,77,78,79]. The phagocytosis process involves the outward bulging of the cell membrane to engulf particles, forming a phagosome that later fuses with lysosomes for digestion [74]. However, it allows for the intake of solid particles [72,73]. It is largely restricted to professional immune cells like macrophages [70]. Large or irregular MPs can lead to “frustrated phagocytosis,” which exacerbates local inflammation. In the case of endocytosis, specific mechanisms include clathrin-dependent endocytosis, caveolin-mediated endocytosis, and macropinocytosis [75]. These pathways can trigger various toxicological responses based on particle size and cell type [78,79].

4.2. Factors Influencing Internalization

Several physicochemical properties determine the efficiency of MNP uptake, including size and shape, surface chemistry, and cell types [70,71,72,73]. Smaller particles are more readily internalized due to evolutionarily conserved mechanisms favoring the uptake of small entities. Surface modifications, such as charge or hydrophobicity, dictate membrane interactions. For instance, hydrophobic MPs tend to adsorb onto membranes, triggering mechanical disruption rather than full internalization. The specific biological context and the health of the cell (e.g., barrier-compromised cells) significantly influence uptake efficiency. In the TME, MNPs accumulate via “leaky” vasculature and become sequestered in the extracellular matrix (ECM), where they act as chronic irritants that drive tumor progression (Figure 3).

4.3. The Distinct Uptake and Internalization of MPs and NPs

The distinction between MPs and NPs is defined by their size-dependent interactions with cellular environments. While MPs are generally too large for passive entry and rely on specialized, restricted mechanisms like phagocytosis by professional immune cells or micropinocytosis [70,71,78,79], NPs are comparable in size to viruses and exosomes, allowing them to utilize multiple evolutionarily conserved endocytic pathways, such as clathrin- and caveolae-mediated endocytosis. Furthermore, unlike MPs, very small NPs may even undergo energy-independent diffusion across lipid bilayers. This size disparity also affects surface behavior. MPs often remain surface-adherent, inducing membrane stress and mechanical disruption, whereas NPs rapidly form a biomolecular corona that facilitates receptor-mediated uptake and efficient intracellular trafficking [70,71,78,79]. The biological impacts of these particles differ significantly. MPs primarily cause mechanical irritation and chronic inflammation when trapped in the extracellular matrix. In contrast, NPs are attributed with the ability to access organelles, leading to systemic oxidative stress, genotoxicity, and metabolic changes.

5. Human Exposure Pathways to Microplastics (MPs)

Microplastics (MPs) are ubiquitous environmental contaminants that pose significant health risks through two primary exposure routes: inhalation and ingestion. Airborne MNPs originate from the fragmentation of plastic litter, industrial emissions, and friction from synthetic textiles and tires [53,68,80,81]. Due to their ability to linger in the air, these particles are easily inhaled, reaching the deep respiratory tract [69,80]. Inhaled MNPs stimulate the generation of reactive oxygen species (ROS), leading to inflammation, oxidative stress, and cellular damage [23,53]. Long-term exposure is linked to chronic disorders such as bronchitis and asthma. Furthermore, MNPs act as vectors for pathogens and toxic chemicals, exacerbating respiratory illness [19,82]. Research indicates that MPs may cross the alveolar–capillary barrier to enter the bloodstream, potentially reaching the brain and liver [81]. Humans consume MNPs through contaminated food supplies, including seafood, salt, and bottled water [68]. Drinking water is considered a particularly critical direct route of consumption [82,83]. Upon ingestion, MNPs can trigger inflammation and alter the integrity of the intestinal barrier [84]. Similar to the inhalation route, ingested MNPs can translocate from the gastrointestinal tract into the systemic circulation, allowing them to accumulate in various tissues and organs [81,85].

6. Mechanisms and Evidence of MNPs in Cancer

Although MNPs show some differences in size, they exert significant indirect carcinogenic pressures [20,86,87,88,89]. These carcinogenic pressures mediated by MNPs include oxidative stress, inflammatory signaling, endocrine disruption, and their ability to shuttle environmental toxicants within the cellular and tissue environment [84,87,90,91,92]. MPs interacting with human cells induce oxidative stress, causing DNA damage and cellular dysfunction, which are the fundamental processes in cancer development [64,93,94]. Additionally, MPs trigger pro-inflammatory responses, creating an inflammatory microenvironment conducive to tumorigenesis [74,88,95,96,97,98,99].

Stroma and ECM Modulation

The TME is considered as an active, reciprocal signaling network consisting of stromal and immune cells, the extracellular matrix (ECM), and diverse biochemical signals that shape the TME [26,33,77,100,101]. MNPs are suggested as additional agents within the TME that can disrupt the homeostasis of this compartment through mechanical stress, cellular reprogramming, and vascular remodeling [26,33,101,102]. Unlike classic soluble carcinogens, MNPs, particularly larger microplastics ranging from ~1 µm to 5 mm, act as persistent physical irritants within the TME. These particles can become surface-adherent, inducing significant membrane stress rather than their true intracellular localization. These MNPs can potentially elicit a sustained wounding response that can reorganize the ECM to promote tumor cell migration and distribution [103,104].

Another stromal influence of MNPs can be explored for fibroblast reprogramming. Chronic inflammation and oxidative stress induced by MNP exposure are considerable drivers of tumor progression [13,105]. These factors can trigger the activation of quiescent fibroblasts into cancer-associated fibroblasts (CAFs), which then actively remodel the TME to support angiogenesis, immune evasion, and metastasis [106]. This MNP-driven “activated stroma” creates a permissive environment that facilitates tumor initiation and provides a protective niche. The accumulation of MNPs within the TME architecture can physically interfere with the local niche. Hypoxic conditions within tumors are known to promote genetic instability and angiogenic signaling [107,108]. MNP-induced stress may exacerbate these pathways, promoting the formation of new vasculature to supply the tumor [88,107,108]. Furthermore, MNPs involved in the vasculature can facilitate the extravasation and further accumulation of NPs (<1 µm) deep within the tumor core due to their enhanced ability to cross biological barriers [109,110].

An additional emerging aspect of MNP-TME interplay could be the long-term sequestration of particles. MNPs have been detected in various human tissues, including tumors [13,20,26,27,97,111,112]. Due to their strong surface reactivity, they act as carriers for hazardous chemicals such as phthalates and bisphenol A (BPA) [19]. Once sequestered in the TME, MNPs can continuously leach these endocrine-disrupting additives or adsorbed co-contaminants like PAHs and heavy metals, creating a persistent reservoir of concentrated carcinogens that drive genomic instability and epigenetic remodeling [38,113,114]. A cell culture-based study suggested the potential role of polyethylene MPs in the progression of glioblastoma cancer cells [115]. In the same line, MNPs are suggested to induce EMT in respiratory epithelial cells and have potential implications in carcinogenesis [116]. In an animal model, data suggested the involvement of MPs in tissue damage and potential carcinogenicity during liver infection [117].

7. Oxidative Stress and Chronic Inflammation: Concerted Role

The interaction of MNPs with epithelial and immune cells can contribute to the generation of ROS and subsequent impairment of cellular antioxidant defenses [94,118,119,120]. Specifically, MNPs have been shown to suppress the Nrf2–Keap1 pathway, thereby limiting the expression of essential antioxidant enzymes, including SOD1, CAT, and GPx [99,118,119,120]. This resulting redox imbalance promotes oxidative DNA lesions, including 8-oxo-dG and direct strand breaks [71,118]. Furthermore, MNPs can influence mitochondrial membrane potential and integrity, which can potentially lead to ROS leakage from damaged mitochondria. Such persistent mitochondrial stress can amplify oxidative injury and contribute to genomic instability, a fundamental hallmark of early carcinogenesis [118,119,120].

This oxidative damage is connected with chronic inflammation, which conditions tissues for tumor establishment through persistent immune stimulation and sustained ROS production [121,122,123,124,125]. MNPs are reported to activate pattern-recognition receptors, such as TLR2 and TLR4, leading to the induction of NF-κB–mediated expression of pro-inflammatory factors, including IL-6, TNF-α, IL-8, and COX-2 [97,99,126]. Additionally, MNP-induced cellular stress can potentially activate the NLRP3 inflammasome, stimulating the release of IL-1β and IL-18 [127]. Pro-inflammatory cytokines, particularly IL-6, are suggested to induce JAK/STAT3 pathway, that can indirectly link MNP exposure to increased cell proliferation, metabolic reprogramming, and immune tolerance [97,99,122,123,124]. From the perspective of TME and MNP interactions, sustained cytokine production induced by MNPs can be an indirect player in the pro-cancer landscape. Additionally, chronic inflammation and oxidative stress are critically implicated in the activation of quiescent fibroblasts into CAFs. And these modulated CAFs are known for their role in shaping pro-tumor microenvironment by remodeling the ECM. In summary, the combined pressure of oxidative stress and chronic inflammation mediated by MNPs can indirectly influence signaling networks and tissue homeostasis, promoting the genomic instability and epigenetic remodeling required for cancer development.

8. Epigenetic Dysregulation

In parallel, MNPs are suggested to induce epigenetic perturbations, including changes in DNA and histone methylation. Such changes induced by MNPs can potentially contribute to dysregulation of gene networks controlling inflammation, apoptosis, and cell cycle progression [123,124,125,128,129,130,131]. MNPs are suggested to alter the expression of DNA methyltransferases (DNMT1, DNMT3A, DNMT3B), which are responsible for promoting hypermethylation of tumor suppressor genes (e.g., p16, PTEN) and global hypomethylation [125,131]. Such epigenomic alterations are associated with chromosomal instability and, in turn, pro-carcinogenic events indirectly mediated by MNPs. MNP exposure to human cells can modulate histone acetylation and methylation through altered HDAC, HAT, and EZH2 activity [123,124,125,128]. These changes promote transcriptional programs that favor inflammation, survival signaling, and stemness as potential attributes of cancer. Additionally, MNPs can alter miRNA and lncRNA expression patterns, further modifying pathways involved in cell cycle regulation, immune signaling, and apoptosis.

9. Endocrine Disruption and Hormone-Mediated Effects

Beyond these biological effects, MPs exert physicochemical stress on the TME by disturbing cellular morphology and by releasing additives such as phthalates and BPA [101,106,113,114]. These leachates further amplify oxidative, inflammatory, and endocrine-disruptive signaling pathways, collectively fostering a microenvironment conducive to tumor progression and metastatic potential [27]. Plastic additives such as phthalates, bisphenol A, and flame retardants can leach from MNPs and can modulate hormone receptors, including estrogen (ER), androgen (AR), and thyroid hormone receptors. MNPs and their derived chemicals are reported to modulate the aryl hydrocarbon receptor (AHR), influencing pathways associated with proliferation, metabolic regulation, and xenobiotic responses. Endocrine-responsive tissues, including breast, endometrium, and prostate, may become more susceptible to hormone-dependent malignant transformation following chronic exposure to MNPs.

10. Co-Pollutant Interactions and Synergistic Toxicity

Owing to their high surface area and hydrophobicity, MNPs are suggested to adsorb and concentrate hazardous pollutants such as heavy metals (Cd, Pb, As), PAHs, PCBs, and pesticides. Emerging research shows that MPs can exacerbate the toxicity of co-pollutants such as cadmium [129,130]. In turn, the indirect role of MNPs as a co-pollutant is emerging and needs to be considered in a broader context. MNPs can indirectly enhance the local bioavailability and uptake of carcinogens. Complexes such as Cd-MNP mixtures have shown amplified effects on ROS generation, chromosomal damage, and activation of ERK or NF-κB pathways. Synergistic interactions between MNPs and co-contaminants drive DNA damage and pro-oncogenic signaling. These combined effects significantly surpass those of isolated MNPs.

11. Physical and Structural Disruption (Particle–Cell Interactions)

Irregular or weathered MNPs can physically disrupt cellular membranes, leading to cytoskeletal stress, lysosomal destabilization, and altered membrane integrity [111,112,113,114,115]. While the majority of MNPs do not readily enter the nucleus, indirect triggering of downstream effects, such as ER stress, lysosomal rupture (cathepsin release), and altered vesicular trafficking, can be potentially linked with oncogenic signaling switches.

12. Microbiome–MNP Axis

Ingested MNPs are potentially suggested to influence the gut microbiota, reducing beneficial taxa and promoting pro-inflammatory species [98,132]. Dysbiosis due to MNPs can increase intestinal permeability (“leaky gut”) and enhance the translocation of inflammatory metabolites [105]. Altogether, MNP-induced microbiome alterations contribute to chronic low-grade inflammation, compromised barrier function, and microbial production of carcinogenic metabolites in tumorigenesis.

In summary, MNPs can contribute to carcinogenesis through multiple interconnected mechanisms, including oxidative stress, chronic inflammation, epigenetic alterations, endocrine disruption, interactions with co-pollutants, structural and immunological disturbances, and modulation of the microbiome. These pathways collectively promote genomic instability, disrupt tissue homeostasis, and reshape signaling networks that support tumor initiation and progression. Within the TME, MNPs are increasingly recognized as modulators of inflammation, oxidative injury, epigenetic dysregulation, and ECM remodeling; however, their precise mechanistic contributions remain insufficiently defined. A summarized model of the pro-cancer mechanisms of MNPs is illustrated in Figure 4.

In Vitro and Preclinical Evidence

While micro- and nanoplastics (MNPs) have been detected in both human and animal tumors [13,27,97,112], insights into their carcinogenic potential remain largely theoretical. Most data stem from general in vitro toxicity studies rather than direct in vivo validation within the TME. Consequently, critical evidence gaps persist regarding physiologically relevant exposure levels, long-term tissue retention, and clearance dynamics. Current in vitro platforms, including 3D and organoid systems, fail to simulate MNP interactions with the extracellular matrix (ECM) or complex tumor–stromal architecture. In clinical settings, the lack of standardized criteria for assessing MNP–tumor colocalization, compounded by the high risk of sample contamination, hinders clear interpretation. Furthermore, the underutilization of spatial and single-cell omics limits our understanding of how MNPs reshape gene expression and cellular behavior. There is no consensus on the use of negative control polymers, making it difficult to attribute carcinogenicity solely to plastic properties. Additionally, studies frequently employ high doses that do not reflect environmental reality, complicating the determination of dose–response relationships or latency periods. The broader research landscape is constrained by limited epidemiological data and the inherent difficulty of extrapolating results from animal models to humans due to species-specific variations. Furthermore, the presence of confounding co-pollutants, such as heavy metals, often obscures the interpretation of MNP-specific effects, making it nearly impossible to isolate the primary driver of carcinogenicity.

Associations between MP exposure and an increased risk of cancer have been reported by epidemiological studies. For instance, one recent work discovered that MP exposure was positively associated with the development of oral carcinoma and other types of cancer [133]. In addition, human organs, including the gastrointestinal tract and respiratory tract, have been found to contain MPs, and their exposure has been shown to provoke inflammation and organ dysfunction [54,133]. The impact of MPs is further complicated by their role as vectors of toxic chemicals. MPs absorb and transport toxic materials, including polycyclic aromatic hydrocarbons (PAHs), which are established carcinogenic agents [133].

Ingesting MPs has serious health implications. Well-established consequences of MP exposure have been documented, causing oxidative stress and inflammation in the gut, and resulting in intestinal diseases including inflammatory bowel disease (IBD) and colorectal cancer (CRC) [85,134]. Moreover, MPs have been implicated in altering gut microbiota with implications for human health. Dysbiosis in gut microbiota can contribute to metabolic diseases, immune disorders, and even neurological disorders [65,135]. MPs and per- and polyfluoroalkyl substances (PFASs) are indicated to display toxicity in aquatic environment and also reported for cytotoxicity in human cells [136,137].

13. Detection and Characterization of MNPs

The investigation of MNPs within the TME relies on a multi-staged methodology involving sampling, isolation, and advanced chemical analysis [24,27,138,139,140,141,142,143]. While surgical biopsies remain the primary source for tissue analysis [142], liquid biopsies, such as blood and urine, offer a non-invasive alternative for monitoring systemic exposure. Following collection, MNPs are isolated from complex biological matrices using density separation and membrane filtration [138]. However, the subsequent identification process must balance morphological data with chemical specificity to ensure clinical relevance. Current research favors a tripartite approach to characterization, though each method presents distinct spatial and sensitivity limits. Widely utilized for tissue samples, µFTIR is physically constrained by the diffraction limit of infrared light. Standard setups generally overlook particles smaller than 20 µ, potentially missing the smaller MNPs most likely to cross blood–tissue barriers or undergo cellular uptake. Micro-Raman spectroscopy is considered superior for intracellular investigation. Raman spectroscopy provides higher spatial resolution down to 1 µ. This capability is critical for identifying MNPs embedded within individual cancer cells, though biological autofluorescence often hampers practical detection in clinical biopsies [24]. Unlike optical techniques, Py-GC/MS provides mass-based quantification (e.g., ng of plastic per gram of tissue). As a “size-blind” method, it captures the total plastic load, including nanoplastics, providing a comprehensive view of polymer exposure that microscopy might underestimate. Quantification typically employs advanced image analysis software to determine particle count, size, and morphology [139]. To enhance sensitivity, emerging technologies such as microfluidic devices allow for high-throughput sorting [141]. Machine learning-based assays are also being developed for indirect evaluation of MNP exposure [140]. Despite these advancements, the field faces significant hurdles. Non-standardized protocols and reference materials cause data inconsistency. Additionally, cross-contamination from lab equipment and air can yield false positives. The temporal stability of MNPs in tissue also remains unknown, complicating our understanding of how plastic accumulation drives cancer.

On a regulatory level, while no legally enforceable maximum contaminant level (MCL) has been globally finalized to date, significant strides have been made toward reaching a consensus. The U.S. EPA recently added MPs to the Contaminant Candidate List (CCL 6), signaling a move toward federal regulation. Similarly, the EU’s Recast Drinking Water Directive now requires harmonized monitoring across member states. These agencies are currently prioritizing the establishment of standardized monitoring baselines over fixed limits, as the diversity of polymer types and the lack of detection limits for NPs continue to complicate the definition of a universal “safe” threshold.

14. Public Health Implications and Regulatory Responses to MP Pollution

MNPs are considered ubiquitous environmental contaminants with profound implications for human health [11,12,13,14,15,16,17,18,19,20]. Found across air, water, and food sources, these particles enter the human body via ingestion, inhalation, and dermal contact. The escalating global concern over MNP pollution has prompted governments to implement strategic interventions. Many nations have prohibited “intentionally added” MPs in consumer products, such as exfoliants and toothpastes (e.g., EU Regulation 2023/2055). Organizations such as the UNEP, OECD, and the Global Plastics Treaty are advocating for comprehensive life-cycle regulations to mitigate plastic leakage at its source. The World Health Organization (WHO) has called for systematic risk assessments regarding MPs in drinking water, emphasizing the need for interdisciplinary research into long-term health outcomes.

To address MNP contamination, enhancing recycling and waste facilities is critical to prevent macroplastics from degrading into MPs. Proper disposal reduces the demand for virgin plastics and keeps waste out of the environment. New wastewater treatments, including advanced filtration and enhanced biodegradation, can be helpful in improving MNP removal rates. Developing eco-friendly, biodegradable composites could offer a sustainable path to reducing the persistence of plastic particles. Public education can serve as a dual-action catalyst. By informing consumers of the risks associated with MP exposure, individuals can shift market demand away from single-use plastics and over-packaged goods. Furthermore, increased public awareness may exert necessary pressure on policymakers to fund research and tighten industrial regulations.

15. Gaps and Future Directions

Despite growing interest, the current scientific foundation established thus far regarding MPs and their carcinogenic nature remains highly underdeveloped, and further study is required.

• One such major gap lies in longitudinal human studies since most studies concerning the potential carcinogenic effects of MPs have been conducted on animals or cell lines; while these are informative, they have notable limitations.
• Although existing evidence suggests that the possibility of chronic exposure to MPs can lead to the bioaccumulation of these substances in several tissues, no large human study explains the real risk of cancer induced through such exposures.
• Mechanisms whereby MPs induce inflammation, oxidative stress, and DNA damage have also been reported; more research has to be conducted on them to validate those effects on human tissues. This includes a deeper understanding of how MPs interact with the human immune and endocrine systems because they can play critical roles in cancer progression by disrupting these systems.
• Most current studies focus on specific types of MPs, like polystyrene or polyethylene, while disregarding comparative effects between different polymers and their particle sizes. Considering that MPs may display considerable differences in toxicological impact, more research should be conducted in this regard.
• The preponderance of short-term research provides further support for the need for long-term studies. Chronic exposure studies are necessary to evaluate the bioaccumulation of MPs and their cumulative effect on organs. Most cell mutations leading to cancer can only be manifested after years of exposure. The importance of long-term epidemiological studies is therefore critical for detecting accurately associated cancer risk.
• Additionally, multigenerational animal studies are crucial for establishing the real hereditary or epigenetic health risks associated with exposure to MPs across generations.
• Innovative experimental approaches may be explored to understand the intracellular and extracellular effects of MPs that could influence the cellular conductivity of normal tissue, one of the major factors that can potentiate the initiation and development of tumors.
• Novel approaches can be developed that can precisely estimate components of MPs at intra-organelle, intracellular, and extracellular levels within the TME.
• The potential involvement of MPs in stemness and EMT processes could be evaluated in the context of epigenetic remodeling that could be one of the crucial changes in carcinogenetic processes.
• Last but not least, the establishment of human cohort studies with differing intensities of exposure to MPs is extremely vital in providing an apparent view of long-term impacts such as cancer events. These studies should be implemented across diverse regions worldwide to account for differential exposure factors related to lifestyle and environmental conditions.
• Addressing these research gaps will improve our understanding of the long-term health implications of MPs and their role in cancer development.
• Preclinical and clinical evaluation and guidelines on the use of MPs in various components of molecular, nanomedicine, biosensors, and drugs for various diseases need to be emphasized to lessen carcinogenic effects as a secondary outcome of primary diseases.
• With increasing human activity in space, the possibility of generation and accumulation of MPs in extraterrestrial habitats (e.g., space stations, spacecraft) and their exposures may be the focus of future studies to identify associations with diseases such as cancer.

Currently, proposed models linking MPs and cancer are lacking the interdisciplinary collaboration and long-term funding required for progress. Human cohort feasibility is challenged by difficulties in measuring internal exposure and controlling for confounding factors. The absence of validated biomarkers of MP exposure limits clinical translation. Transgenerational effects and epigenetic inheritance with regard to the effects of MPs in cancer are still speculative. There is a lack of a global surveillance system or policy-driven framework linking MP exposure to cancer epidemiology. A comparative table on existing knowledge and gaps is provided in

Table 2. Comparative status on microplastics and cancer with regard to what is known and proposed concepts.

Aspect	What Is Known (Established Evidence)	What Is Hypothesized (Emerging or Proposed Concepts)
Microplastic Presence in Human Systems	Microplastics (<5 mm) are found in human tissues, including lungs, blood, gastrointestinal tract, and even tumors [25,97].	Persistent accumulation of microplastics within the TME may influence carcinogenesis by modulating stromal–immune–vascular interactions.
Oxidative Stress and Inflammation	Microplastics generate reactive oxygen species (ROS) and provoke chronic inflammation in experimental models [87,93].	Continuous oxidative stress from microplastics may act as a co-carcinogenic trigger, facilitating oncogene activation and tumor suppressor inactivation.
Epigenetic Remodeling	Environmental pollutants, including plastics and phthalates, can induce epigenetic changes such as DNA methylation and histone modification [38].	Microplastic exposure could drive epigenetic reprogramming of the TME, influencing cancer cell plasticity, EMT, and immune evasion.
Co-contaminant Carriage	Microplastics bind polycyclic aromatic hydrocarbons (PAHs), heavy metals, and endocrine disruptors [19,36]	The combined exposure to microplastics and adsorbed carcinogens could synergistically elevate mutagenic and oncogenic risks.
Cellular Uptake and Internalization	Microplastics enter cells through phagocytosis and endocytosis [70].	Once internalized, microplastics may disrupt intracellular organelle signaling and induce pro-tumor metabolic shifts.
Experimental Findings	Animal studies and in vitro models demonstrate inflammation, DNA damage, and altered gene expression upon microplastic exposure [27,128].	Chronic, low-dose exposure may reprogram the TME to favor tumor initiation and mimic a “pre-malignant” niche in non-tumorous tissues.
Public Health Implications	Microplastics are recognized as an environmental hazard with potential for systemic toxicity [67].	Microplastic exposure could become a modifiable cancer risk factor, warranting inclusion in cancer prevention frameworks.

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16. Conclusions

• While current data remain preliminary, converging evidence suggests that MPs can act as accelerants of carcinogenesis through oxidative stress, chronic inflammation, and epigenetic disruption, and by serving as vectors of toxic co-contaminants. Hence, the positioning of MPs as not merely inert pollutants but as actively involved in the development and progression of cancer is being emphasized.
• The potential role of MPs in modulating stromal, immune, and endothelial components of the TME highlights a paradigm where environmental particles may reprogram the niche that fosters tumor initiation, progression, and metastasis.
• Bridging toxicology, oncology, molecular genetics, and environmental sciences is the need of the time to evaluate MPs as co-carcinogens and co-promoters of cancer. Therefore, integrated approaches could accelerate translation from bench to policy, guiding preventive frameworks to manage the burdens of MPs in a polluted world that is imposing additional layers of complexity to cancer.
• Evidence of MPs in human biopsies should serve as a call to action for legislative bodies to regulate plastic production, usage, and waste management with a “cancer prevention” perspective. Public health advisories may eventually evolve to include plastic exposure as a modifiable cancer risk factor.
• However, current findings highlight associative links between MPs and cancer-related pathways but fall short of demonstrating a direct role in cancer incidences in the human population. Hence, long-term prospective epidemiological studies are warranted to link MPs with pro-tumorigenic changes leading to cancer.
• The toxicokinetics of MPs, including threshold exposure levels, biodistribution, organ tropism, persistence, and clearance, as well as improved risk assessment models, are needed for better evaluation of the role of MPs in cancer.
• While oxidative stress and inflammation are associated with the uptake of MPs in cellular contexts, precise molecular mechanisms (e.g., direct DNA damage, oncogene activation, tumor suppressor inactivation, and immune escape induction) are still not clear.
• The rationale that MPs can alter stromal–immune–vascular crosstalk requires further investigation using advanced approaches such as co-culture and in vivo models.
• Future studies on MPs as carriers of heavy metals, PAHs, and persistent organic pollutants may be needed, using sound methodological approaches.
• Current findings cannot establish causation between MPs and specific cancer types. Threshold levels for safe exposure of MPs are unknown and may be associated with cancer risk. Preclinical and clinical evidence on inter-individual variability in MP retention and clearance is poorly understood. Preclinical and clinical data gaps prevent MPs from being formally classified as carcinogens within IARC or WHO frameworks. Policy recommendations on MP exposure are based on precautionary evidence rather than quantitative risk assessments.