From exposure to oncogenesis: a review on the multifaceted roles of microplastics in tumor initiation and progression.

Humans encounter MPs through multiple environmental interfaces and daily behaviors, culminating in the distribution of these particles to diverse organs (Table 1 ). Inhalation is a major route: airborne MPs deposit in the distal airways and alveoli, with analyses of non-smokers—using post-mortem specimens, resected lung tissues, sputum, and bronchoalveolar lavage—identifying polymers such as polyethylene (PE) and polypropylene (PP). Lung tissue burdens have reportedly reached 1.42 ± 1.50 MPs/g, providing direct evidence of air-mediated exposure and pulmonary retention [ 25 – 30 ]. Cutaneous entry represents an alternative pathway; MPs, especially NPs, may traverse pores, sweat glands, hair follicles, or breaches in the skin barrier [ 31 ]. The daily application of personal care items containing plastic microbeads further increases the likelihood of NPs penetration through the skin [ 32 ]. The gastrointestinal tract is considered the dominant portal of entry. Although a vast fraction of ingested particles is eliminated in feces [ 33 , 34 ], multiple polymer types have been detected in human tissues. For instance, MPs identified in colorectal cancer resections provide direct evidence of intestinal deposition and local pathological involvement [ 35 , 36 ]. Fecal MPs levels in preschoolers positively correlate with dietary patterns, implicating food and drinking water as substantial sources of intake [ 37 , 38 ]. Taken together, these observations demonstrate the widespread presence of MPs in human tissues and suggest organ-specific accumulation, underscoring the necessity for systematic investigations into associated health risks. Table 1 Prevalence of MPs in various organs, their compositional types, size, concentration, and detection Organ Sample Size Polymer Type Shape of Microplastics Size of Microplastics Abundance of microplastics Method of Detection References brain 24 PE, PP shards flakes 100–200 nm 4917 µg /g ATR-FTIR [ 39 ] Blood vessels 17 PET, PVC NA > 700 nm 118.66 ± 53.87 µg/g Py-GC/MS [ 40 ] Heart 15 NA NA 20–500 μm NA laser direct infrared [ 41 ] Liver 11 NA fragment, microbead 4–30 μm 0–13 particles per sample or 3.2 particles/g tissue Raman [ 42 ] Placenta 62 PE, PVC fragment, fibre, particle > 1 μm 126.8 ± 147.5 µg/g tissue Py-GC-MS [ 43 ] Spleen 3 NA fragment, microbead 5–25 μm 4 particles per sample or 1.1 particles/g tissue Raman [ 42 ] Lung 13 PP, PET, fragment, fibre 1.6–16.8 μm 1.42 ± 1.50 MP/g µ-FTIR [ 26 ] Testis 6 PS fragment, 20–100 μm 11.60 ± 15.52 particles/g Py-GC/MS [ 44 ] semen 30 PE, PVC fragments, fiber, film 20–100 μm 0.23 ± 0.45 particles/mL Py-GC/MS [ 44 ] bone marrow 16 PE, PS, PVC fragments < 100 μm 51.29 µg/g Py-GC/MS [ 45 ] thrombus 30 PE PVC fragment spherical 20–50 μm 69.62 µg/g Py-GC/MS [ 46 ] endometrium 20 ACR, PE irregular-shaped 20–100 μm 0-117 particles/100 mg laser direct infrared [ 47 ] amniotic fluid 40 PE, CPE fragments 20–100 μm 2.01 ± 4.19 particles/g LD-IR [ 48 ] Uterus 22 PA, PU, PET NA 2–200 μm NA Raman [ 49 ] Prevalence of MPs in various organs, their compositional types, size, concentration, and detection shards flakes PE PVC fragment spherical ACR, PE Current understanding of MPs distribution in the human body is primarily derived from limited analyses of human tissue samples. While these studies provide valuable insights into systemic exposure, they do not entirely depict the dynamic distribution patterns of MPs across different organs. Animal models have augmented this knowledge by elucidating the biological distribution, accumulation dynamics, and underlying mechanisms of MPs (Table 2 ). Several rodent studies employing polystyrene (PS) particles of varying sizes (40 nm to 50 μm) and doses (0.125 mg/mL to 50 mg/kg) have revealed complex distribution patterns in vivo. These studies indicate that orally administered PS-MPs are absorbed through the gastrointestinal tract and significantly accumulate in parenchymal organs, such as the liver and kidneys. Some particles even breach the intestinal barrier and migrate to distant organs [ 50 ]. This transbarrier migration results in widespread MPs distribution throughout the body, leading to organ-specific toxicity. PS-MPs exposure in the mouse reproductive system leads to accumulation in the ovaries, uterus, testes, and sperm, resulting in diminished sperm quality and impaired ovarian follicle development, ultimately compromising fertility [ 51 ]. In the respiratory system, polystyrene nanoparticles (PS-NPs) can induce chronic obstructive pulmonary disease (COPD)-like lesions and pulmonary fibrosis, as well as disrupt lung metabolism. The liver, a major target for MPs accumulation, exhibits signs of inflammation, fibrosis progression, and lipid metabolic disorders [ 52 ]. In the kidneys, tissue damage and the formation of a pro-fibrotic microenvironment have been observed. Notably, the toxic effects of MPs are considerably size-dependent and demonstrate dose-related responses. Smaller-sized NPs can cross the blood-brain barrier, causing neuronal damage in the hippocampus and impairing learning and memory [ 53 ]. In the cardiovascular system, PS-MPs induce myocardial oxidative stress and cell apoptosis, leading to cardiac fibrosis and dysfunction. Additionally, MPs can trigger multi-organ interactions through pathways such as the gut–liver axis, forming a systemic health risk network. However, translating existing experimental findings into human health risk assessments presents significant challenges. A primary limitation arises from the marked disparity between experimental conditions and actual human exposure scenarios. Most current toxicity studies employ MPs doses that substantially exceed environmentally relevant concentrations [ 54 , 55 ], and often utilize exposure routes distinct from those in humans, thereby hindering the identification of a biologically relevant effect dose. Furthermore, experimental models primarily rely on acute exposure designs, which fail to adequately simulate the long-term, low-dose cumulative exposure patterns characteristic of human interaction with MPs. For risk assessment, the understanding of the fundamental toxicological profile of MPs remains constrained. Critical parameters, such as a definitive dose threshold or the lowest observed adverse effect level, have not been established. In addition, there is a distinct lack of reliable toxicokinetic data and systematic dose-response studies. Consequently, it is currently unfeasible to derive a tolerable daily intake or establish safety limits for MPs, as is standard practice for conventional environmental pollutants, which severely impedes the development of health-based guidance values. Moreover, current knowledge is largely derived from studies using uniform PS-MPs, which differ significantly in composition, morphology, and aging state from the complex and diverse mixtures of MPs encountered in the environment, thus limiting the ecological relevance of the findings. Key questions regarding the specific translocation pathways of MNPs across biological barriers, their long-term retention effects, and distribution kinetics under varying physiological conditions also remain to be elucidated. Therefore, future research must prioritize investigations into the fate and behavior of MPs under realistic, environmentally relevant exposure conditions involving complex mixtures. This is essential to advance our understanding of their biodistribution and accumulation mechanisms, thereby providing a critical scientific foundation for a comprehensive assessment of human health risks. Table 2 Summary of MPs characteristics, tissue retention, and biological effects in animal studies Biotoxicity Microplastics Size Concentration Cycle Biological effect References Reproductive toxicity PS-MPs 1 μm 1, 5 mg/kg 4 w oxidative stress, inflammation, and premature testicular aging [ 56 ] PS-MPs 5 μm 5 mg/kg 35 d low sperm quality and increased sperm deformity [ 57 ] PS-MPs 5 μm 80 nm 0, 10, 40 mg/kg/d 60 d apoptosis of spermatogenic cells [ 58 ] PS-MPs 0.2, 2, 10, 50 μm 5 mg/kg 14, 30 d decreased fertility [ 49 ] Lung injury PS-MPs 40 mg/kg 30 d reduced oocyte maturation, fertilization rate [ 59 ] PS-NPs 40 nm 16, 40, 100 µg/d 12 w COPD; lung injury [ 60 ] PS-NPs 100 nm 0.25 mg/kg/d 6 w Fibrosis; pulmonary metabolic disorder [ 61 ] Hepatic Injury PS-MPs 1–10 μm 1 mg/kg 30 d activated hepatic inflammation, promoted fibrosis [ 62 ] Kidney Injury PS-MPs 1 μm 10 mg/L 18 w kidney injury pro-fibrotic microenvironment, [ 63 ] Cardiotoxicity PS-MPs 0.5 μm 0.5, 5, 50 mg/L 90 d cardiac fibrosis and dysfunction; oxidative stress and apoptosis of myocardium. [ 64 ] PS-MPs 1 μm 25, 50 µg/d 4 w abnormal heart rate, apoptosis of cardiomyocytes, mitochondrial membrane potential change, and fibrin overexpression. [ 65 ] Nervous system PS-MPs 0.1, 2 μm 0.125 mg/mL 3w learning and memory decreased [ 53 ] PS-NPs 80 nm 60 µg/d 42 d neuronal damage in the hippocampus, affect the learning and memory ability [ 66 ] Multi-organ crosstalk PS-MPs 1 μm 2, 10 mg/kg/d 21 d intestine-liver axis disorders; gland injury [ 67 ] Summary of MPs characteristics, tissue retention, and biological effects in animal studies 1, 5 mg/kg oxidative stress, inflammation, and premature testicular aging 5 μm 80 nm 14, 30 d Kidney Injury kidney injury pro-fibrotic microenvironment, 25, 50 µg/d 2, 10 mg/kg/d As evidence of MPs and NPs accumulation in various human tissues continues to grow, attention is increasingly focused on the toxic mechanisms triggered by such exposure. Currently, MPs detection in human tissues principally relies on a combination of microscopic techniques, spectroscopic methods, and mass spectrometry (Table 3 ). Optical and electron microscopy provide initial morphological insights into the particles [ 68 , 69 ], while spectroscopic methods identify MPs by analyzing spectral lines generated from energy-induced molecular vibrations. Fourier-transform infrared and Raman spectroscopy are the two predominantly used spectroscopic techniques [ 70 , 71 ]. For quantification, chromatography-mass spectrometry methods, such as liquid chromatography-mass spectrometry (LC-MS) and pyrolysis-gas chromatography-mass spectrometry (Py-GC/MS), are employed for qualitative and quantitative analyses of MPs. Py-GC/MS generates precise mass concentration data [ 38 , 64 ], while LC-MS effectively detects soluble plastic additives [ 72 ]. Nevertheless, these methods often necessitate digestion treatments for tissue samples [ 23 , 73 , 74 ]. Although such treatments effectively minimize biological matrix interference and facilitate chemical analysis, they inevitably disrupt the spatial distribution information of MPs within the tissue, thereby hindering accurate in situ localization. Furthermore, the complex structure and chemical composition of MPs—coupled with significant interference from proteins, lipids, and other biological components—present limitations in accuracy, resolution, and applicability [ 75 ]. The lack of standardized identification processes and quality control systems also impedes the comparison and integration of research findings across studies. Emerging in situ imaging technologies, such as secondary ion mass spectrometry, hold significant promise. These techniques enable the direct acquisition of particle distribution data in tissues without requiring sample digestion, thereby offering new insights into the tissue-specific accumulation and migration behaviors of MPs and NPs [ 76 , 77 ]. Additionally, artificial intelligence technologies, including machine learning [ 78 , 79 ], are increasingly applied to automatically recognize and classify spectroscopic data. These technologies effectively differentiate MPs signals from biological matrix interference and can rapidly identify complex particle mixtures, enhancing detection accuracy and efficiency. Establishing international standards for MPs and NPs detection in biological samples is a widely supported endeavor within the scientific community and remains a crucial challenge for assessing the distribution, migration, and accumulation of these particles in living organisms. Table 3 Analytical techniques for MPs quantification [ 5 , 39 , 55 , 81 , 82 ] Methods Advantages Limitations Microscopic observation Characterize MPs morphology; Non-destructive. Unidentifiable polymer composition. Nile Red fluorescence microscopy Rapid microscopic quantification. Unidentifiable polymer composition; Risk of matrix interferences. PLM Non-invasive detection; High-contrast imaging; Preliminary classification. Not suitable for NPs; Uncertain polymer composition. SEM-EDS Determine particle number; Information on size and shape. No polymer identification; Requires thorough matrix removal; Limit of detection: ~0.1 μm. µ-FTIR/FTIR Enable polymer identification; Determine particle number; Information on size and shape. Offer precise and reliable results. Not suitable for NPs; Risk of matrix interferences; Limit of detection: ~10 μm; Destroy surface morphology of the sample. LDIR Enable polymer identification; Determine particle number; Information on size and shape. Not suitable for NPs; Risk of matrix interferences; Extensive sample pre-treatment. Limit of detection: ~10 μm. µ-Raman/Raman Enable polymer identification; Determine particle number; Information on size and shape. Offer precise and reliable results. Non-destructive to the MPs particles. Not suitable for NPs; Susceptible to fluorescence interferences; Limit of detection: ~1 μm. Requires meticulous sample preparation. Prolonged processing time. Py-GC/MS Enable polymer identification; Broad applicability; Quantitative and qualitative analysis; No size detection limit. Limited size information; Risk of matrix interferences; Prolonged processing times. Destructive technique. LC-MS High sensitivity; Targeted MPs quantitation. Limited applicability; Complex sample preparation. Analytical techniques for MPs quantification [ 5 , 39 , 55 , 81 , 82 ] Characterize MPs morphology; Non-destructive. Unidentifiable polymer composition; Risk of matrix interferences. Non-invasive detection; High-contrast imaging; Preliminary classification. Not suitable for NPs; Uncertain polymer composition. Determine particle number; Information on size and shape. No polymer identification; Requires thorough matrix removal; Limit of detection: ~0.1 μm. Enable polymer identification; Determine particle number; Information on size and shape. Offer precise and reliable results. Not suitable for NPs; Risk of matrix interferences; Limit of detection: ~10 μm; Destroy surface morphology of the sample. Enable polymer identification; Determine particle number; Information on size and shape. Not suitable for NPs; Risk of matrix interferences; Extensive sample pre-treatment. Limit of detection: ~10 μm. Enable polymer identification; Determine particle number; Information on size and shape. Offer precise and reliable results. Non-destructive to the MPs particles. Not suitable for NPs; Susceptible to fluorescence interferences; Limit of detection: ~1 μm. Requires meticulous sample preparation. Prolonged processing time. Enable polymer identification; Broad applicability; Quantitative and qualitative analysis; No size detection limit. Limited size information; Risk of matrix interferences; Prolonged processing times. Destructive technique. High sensitivity; Targeted MPs quantitation. Limited applicability; Complex sample preparation. Early epidemiological findings indicate a tentative association between MPs exposure and cancer risk [ 32 ]. Human histologic studies have reported MPs enrichment within tumor tissues from colorectal [ 36 ], penile [ 82 ], and prostate [ 83 ], with concentrations exceeding those in adjacent non-malignant tissues. Notably, particles often colocalize with inflammation foci [ 84 ], suggesting a role in microenvironmental alterations that facilitate malignant transformation. Clinical observations in inflammatory bowel disease provide additional support: fecal MPs concentrations increase with disease activity [ 85 ], indirectly corroborating a potential “MP exposure–intestinal inflammation–carcinogenesis” pathway. Occupational cohorts with chronic exposure to high plastic dust, including workers in plastics manufacturing and textile processing, exhibit modest elevations in lung and bladder cancer incidence [ 86 – 88 ]. In community settings, MPs constituents have been identified within PM2.5 samples [ 89 ], with regional abundance spatially correlating with lung cancer patterns [ 90 ]. Additional organ-specific signals have emerged: in liver disease, MPs presence in the hepatic tissue of individuals with non-alcoholic fatty liver disease correlates with progression toward fibrosis and hepatocellular carcinoma [ 91 ]. In gynecologic pathology, polytetrafluoroethylene concentrations are higher in endometriosis lesions than in normal endometrium [ 92 ], suggesting possible contributions via chronic inflammation and interactions with estrogen-receptor signaling. Notwithstanding these initial observations, a cautious interpretation is warranted due to significant methodological constraints in the current epidemiological literature on the microplastic-cancer link. First, exposure assessment lacks precision, as most studies rely on indirect methods like environmental monitoring or occupational history to estimate exposure levels rather than directly quantifying MPs burdens in human biological samples, which hampers the establishment of reliable dose-response associations. Second, potential confounding factors, including diet, lifestyle, and co-exposure to other pollutants, are often inadequately controlled in existing research, raising concerns about residual bias. Most critically, the current evidence is predominantly derived from cross-sectional or retrospective designs, with a scarcity of prospective cohort data needed to establish a clear temporal relationship between exposure and outcome. Moreover, the inherent complexity of MPs complicates the attribution of health effects. In the environment, microplastics typically exist as complex mixtures with other contaminants, making it difficult to discern whether observed adverse effects stem from the physical presence of the particles, the leaching of chemical additives, or the toxicity of adsorbed pollutants. Furthermore, factors such as long-term, low-dose exposure scenarios, individual susceptibility, and the high heterogeneity of microplastic particles add further layers of complexity. Consequently, future research should focus on integrating standardized biomonitoring protocols into large-scale, multi-center prospective cohorts to refine individual exposure characterization. Equally critical is conducting systematic dose-response analyses at environmentally realistic concentrations to derive no-observed-adverse-effect levels, coupled with advancing sensitive techniques for detecting and quantifying MPs in tissues. These efforts are indispensable to providing a robust foundation for scientific risk assessment and the formulation of effective public health policies.

Despite the toxic effects of MPs in environmental and human contexts, their adjustable size, high surface area, and functionalizable characteristics render them potential drug delivery carriers [ 198 ]. Smaller-sized NPs can efficiently traverse biological barriers, improving intracellular drug delivery and tissue penetration. By modifying the surface of MPs with targeting ligands, their recognition and accumulation in tumor cells can be significantly enhanced, thus improving treatment precision [ 199 ]. Research has explored the use of MPs as Fe ion carriers or ferroptosis inducers, aiming to enhance cancer treatment effectiveness [ 200 – 202 ]. Developing carriers with pH, temperature, or enzyme-responsive multi-layer structures enables controlled drug release. For instance, NPs composed of polylactic-co-glycolic acid (PLGA) and polylactic acid can provide long-term stability and sustained drug release [ 203 – 205 ]. In the context of immune regulation, lipid/PLGA-based nanocomposite systems have demonstrated promise in activating anti-tumor immunity by reshaping the tumor immune microenvironment, particularly in colorectal cancer treatment [ 206 ]. Nevertheless, the clinical translation of MPs and NPs presents significant biological safety challenges. Current research lacks comprehensive systemic toxicity evaluations and long-term safety monitoring data for medical-grade MPs. Concerns persist regarding potential off-target effects, and the risk of in vivo accumulation may undermine therapeutic benefits. As an example, carrier particles may be non-specifically phagocytosed by immune cells, hindering effective drug accumulation at tumor sites and instead accumulating in organs such as the liver and spleen, potentially causing hepatotoxicity or immune suppression [ 207 ]. Besides, the degradation of MPs and NPs may release additives or intermediates that could exert unknown effects on normal cells. Future research should prioritize the development of functionalized carriers with high biocompatibility and targeting efficiency, minimizing off-target risks, and establishing standardized long-term safety evaluation systems. These advancements are crucial for transitioning from conceptual validation to clinical application, ensuring the safe and effective use of MPs and NPs in cancer treatment.

MPs can disrupt the physical barrier functions of various organs, facilitating subsequent inflammatory responses and tumorigenesis. MPs exert significant disruptive effects on multiple physiological barrier systems. In the airway epithelial barrier, MPs interact with pulmonary surfactants, forming heterogeneous aggregates that alter alveolar surface tension and disrupt ultrastructure [ 93 – 95 ]. When co-exposed with dust mites, this disruption exacerbates airway epithelial dysfunction, thereby heightening the risk of respiratory diseases such as asthma [ 96 ]. In the intestinal barrier, MPs decrease the expression of tight junction proteins such as ZO-1 and occludin, leading to increased epithelial permeability [ 97 – 101 ]. In the gastric environment, MPs act as carriers for pathogenic microorganisms, facilitating biofilm formation by Helicobacter pylori and enhancing its colonization ability. The resulting chronic inflammation disrupts the balance between cell proliferation and apoptosis, fostering a microenvironment favorable for tumor formation [ 102 – 106 ]. Dermal exposure also plays a significant role, as certain components in skincare products can enhance NPs permeability [ 107 ], thus compromising stratum corneum integrity [ 108 ]. Physical barrier disruption not only directly results in tissue damage but also facilitates the recognition and contact of MPs by immune cells, initiating an innate immune response. MPs, when bound to pattern recognition receptors such as Toll-like receptors 2 and 4, activate the “nuclear factor kappa-light-chain-enhancer of activated B cells” (NF-κB) pathway through a “myeloid differentiation primary response 88” (My D88) -dependent mechanism, promoting the release of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin (IL) -6 [ 109 – 111 ]. As exogenous substances that are difficult to degrade, MPs persistently activate innate immune receptors at low levels, potentially sustaining a pro-inflammatory environment and leading to immune cell tolerance or functional exhaustion [ 112 , 113 ]. MPs also activate the NLRP3 inflammasome [ 114 ], a mechanism linked to lysosomal damage, ER stress, and mitochondrial ROS generation [ 115 , 116 ], thus playing a pivotal role in transforming physical structural damage into molecular immune response activation. Overall, physical barrier disruption by MPs and NPs is a fundamental mechanism underlying their health risks. This disruption not only directly impairs barrier functions but also provides a pathway for other harmful substances to enter the body, exacerbating the risk of inflammatory diseases and tumorigenesis. By inducing oxidative stress, MPs not only directly trigger multiple PCD pathways but also cause DNA damage and genomic instability, thereby establishing a multifaceted molecular foundation that facilitates tumorigenesis and progression. Owing to their physical properties, chemical additives, or the pollutants adsorbed to their surfaces, MPs induce substantial reactive oxygen species (ROS) production within cells, leading to mitochondrial and endoplasmic reticulum (ER) dysfunction. This dysfunction activates several PCD pathways, including apoptosis, ferroptosis, and pyroptosis [ 14 – 16 ] (Fig. 2 ). Mitochondria are particularly targeted by MPs. Studies indicate that MPs exposure significantly reduces mitochondrial membrane potential and impairs adenosine triphosphate (ATP) synthesis in various cell types, including splenic lymphocytes [ 117 ], sperm [ 118 ], macrophages [ 119 ], and epithelial cells [ 120 , 121 ]. Positively charged NPs tend to adsorb to the negatively charged mitochondrial membrane via electrostatic interactions, accumulating in the matrix [ 117 , 122 ]. This physical occupation disrupts the normal function of the electron transport chain complexes, leading to a surge in ROS generation. Additionally, it may trigger mitochondrial membrane permeabilization, activating the mitochondrial apoptosis pathway through molecules such as Bax, Cyt C, and caspase-9 [ 15 , 123 , 124 ], thereby enhancing cytotoxicity. Apart from directly inducing apoptosis via the mitochondrial pathway, the ROS surge also serves as a central signaling node, activating ER stress. MPs and NPs interfere with calcium ion channel function in the ER, disturbing luminal Ca²⁺ homeostasis and releasing sizeable quantities of Ca 2+ into the cytoplasm [ 125 ]. Elevated Ca²⁺ levels exacerbate mitochondrial dysfunction and activate calcium-dependent proteases, triggering apoptosis in various cell types, including bronchial epithelial [ 123 ], testicular interstitial [ 126 ], renal [ 127 ], gastric mucosal [ 128 ], and ovarian granulosa [ 129 ] cells. In the pyroptosis pathway, MPs activate the NOD-like receptor family pyrin domain-containing 3 (NLRP3) /caspase-1 axis, triggering gasdermin D cleavage, which forms membrane pores and promotes the release of pro-inflammatory cytokines such as IL-1β and IL-18 [ 114 , 130 ]. Furthermore, in tissues such as the lung and liver, MPs-induced ferroptosis [ 131 , 132 ] not only exacerbates tissue damage and local inflammation but also creates a microenvironment conducive to tumor growth [ 123 , 133 , 134 ]. The dysregulation of these PCD pathways constitutes a critical link connecting MPs exposure to the formation of a pro-tumorigenic microenvironment. Beyond its role in regulating cell death programs, MPs-induced oxidative stress directly induces DNA damage. MPs exposure significantly elevates intracellular levels of ROS, which directly attack DNA molecules, causing extensive oxidative damage, such as DNA double-strand breaks, base modifications, and adduct formation. This damage contributes to chromosomal instability [ 14 – 16 ], thereby increasing cancer risk. Several studies have confirmed that MPs-induced DNA damage is dose-dependent, with indicators such as comet assay tail length used to assess the degree of damage [ 51 , 148 , 149 ]. Under combined exposure conditions, MPs synergize with pollutants like arsenic, exacerbating DNA strand breaks and inhibiting essential repair mechanisms, including base excision repair and homologous recombination [ 150 , 151 ]. This results in the accumulation of mutations during DNA replication, driving a reduction in genomic stability and promoting tumor initiation [ 152 , 153 ]. In addition to inducing genetic instability, MPs can directly regulate the malignant phenotype of cancer cells. For example, PS-NPs upregulate stem cell markers such as cluster of differentiation 44 (CD44) and aldehyde dehydrogenase 1 (ALDH1), promoting the expansion of undifferentiated cells and enhancing their migratory and invasive abilities [ 24 , 154 ]. PS-NPs exhibit bioaccumulation and enhance the migratory phenotype in colorectal cancer [ 155 ], while PP-MPs promote cancer progression by upregulating the expression of metastasis-related genes, such as transmembrane BAX inhibitor motif-containing 6 (TMBIM6) and AP2M1 [ 156 ]. TMBIM6 reportedly activates the mammalian target of rapamycin complex 2/protein kinase B signaling pathway (mTORC2/Akt), further promoting metastasis [ 157 ]. In gastric cancer cells, MPs also increase invasiveness and chemotherapy resistance by upregulating ASGR2 [ 158 ]. Evaluating the implications of these findings for human cancer risk necessitates a rigorous assessment of the clinical relevance and evidential weight of each signaling pathway. Currently, the link between MPs and ferroptosis relies heavily on in vitro and rodent models [ 135 – 137 ], meaning the extent to which these processes contribute to human carcinogenesis remains indeterminate. While experimental systems have confirmed critical molecular hallmarks, such as GPX4 inhibition and lipid peroxide accumulation [ 133 ], there is a distinct absence of translational studies confirming the co-localization of MPs accumulation and ferroptosis markers within human tumor specimens. Furthermore, the hypothesized “double-edged” nature of ferroptosis in MPs-driven tumorigenesis—acting either as a driver of malignant transformation in normal tissue or as a suppressor of pre-malignant cells—is largely speculative [ 138 , 139 ]. Consequently, validation in models that better recapitulate human physiological conditions is imperative. Conversely, the susceptibility of mesenchymal or pre-metastatic cancer cells to ferroptosis, due to an iron- and ROS-enriched tumor microenvironment (TME), offers a compelling basis for developing therapeutic interventions designed to exploit this vulnerability [ 140 – 143 ]. Regarding pyroptosis, its magnitude of activation and oncogenic implications within the epithelial progenitor cells of solid tumors remain poorly characterized. While the secretion of inflammatory mediators linked to pyroptosis is hypothesized to cultivate a pro-tumorigenic niche, the functions of these cytokines at different stages of tumor progression are debated, with potential for context-dependent, bidirectional effects [ 144 , 145 ]. Ultimately, the scarcity of clinical or epidemiological data currently precludes a definitive understanding of the role of MPs-induced pyroptosis in human cancer development. Collectively, MPs appear to drive a pro-tumorigenic nexus via oxidative stress, effectively bridging PCD and DNA damage into a synergistic network. However, current evidence is largely derived from cellular-level studies. The long-term cumulative effects of MPs in vivo, the specific pathways underlying their genotoxicity, and the variations in carcinogenic potential among MPs with diverse physicochemical properties remain to be elucidated through systematic in vivo investigations and epidemiological studies. Future research should prioritize the validation of these mechanistic pathways in human biospecimens and the establishment of robust dose-response relationships, which are crucial for accurately assessing the health risks of MPs and developing targeted intervention strategies. Fig. 2 MPs promote TME formation by jointly activating multiple PCD pathways through the induction of oxidative stress and ER stress. This schematic diagram systematically elucidates the relevant molecular mechanisms: exposure to MPs initially induces mitochondrial oxidative stress and ER stress. This dual stress triggers cytochrome c release, activating the caspase-9/caspase-3 cascade to initiate apoptosis. Concurrently, it disrupts calcium homeostasis and elevates calmodulin-dependent kinase activity, accompanied by glutathione depletion and GPX4 downregulation. Collectively, these effects promote lipid peroxidation and induce ferroptosis. Furthermore, these stress signals activate the NLRP3 inflammasome, prompting caspase-1-mediated IL-1β maturation and gasdermin D cleavage to execute pyroptosis. These synergistic PCD pathways, coupled with diminished ATP synthesis capacity, concertedly shape a microenvironment conducive to tumor initiation and progression. The graphical abstract was created using BioRender.com MPs promote TME formation by jointly activating multiple PCD pathways through the induction of oxidative stress and ER stress. This schematic diagram systematically elucidates the relevant molecular mechanisms: exposure to MPs initially induces mitochondrial oxidative stress and ER stress. This dual stress triggers cytochrome c release, activating the caspase-9/caspase-3 cascade to initiate apoptosis. Concurrently, it disrupts calcium homeostasis and elevates calmodulin-dependent kinase activity, accompanied by glutathione depletion and GPX4 downregulation. Collectively, these effects promote lipid peroxidation and induce ferroptosis. Furthermore, these stress signals activate the NLRP3 inflammasome, prompting caspase-1-mediated IL-1β maturation and gasdermin D cleavage to execute pyroptosis. These synergistic PCD pathways, coupled with diminished ATP synthesis capacity, concertedly shape a microenvironment conducive to tumor initiation and progression. The graphical abstract was created using BioRender.com Long-term MPs retention in the body induces persistent inflammation, immune-metabolic reprogramming, and microbial dysbiosis, collectively remodeling the TME. Key features of this remodeling include immune surveillance dysfunction, metabolic disorders, and matrix remodeling, and establishing a vicious cycle with gut microbial dysbiosis, which creates favorable conditions for tumor immune evasion, proliferation, and metastasis. From an immunological perspective, MPs, as non-degradable exogenous substances, cause chronic immune activation and dysfunction. They recruit and activate specific cells, forming an immunosuppressive microenvironment rich in inhibitory cells and cytokines [ 146 ]. The specific size and anti-degradation properties of MPs lead to their long-term retention within immune cells, disrupting normal cellular functions [ 147 ], impairing immune surveillance, and enabling tumor immune escape and metastasis [ 6 , 103 , 148 , 149 ]. In the colon, MPs ingested by macrophages cause lysosomal damage, activate the NLRP3 inflammasome pathway, and result in the maturation and secretion of caspase-1-dependent IL-1β and IL-18 [ 150 , 151 ]. These factors activate the Janus kinase– signal transducer and activator of transcription (JAK-STAT) signaling pathway, disrupting T regulatory and T helper 17cell (Th17) differentiation and inducing T cell exhaustion, thereby creating a profoundly immunosuppressive environment [ 102 – 105 ]. Furthermore, long-term exposure to PS-NPs in mesenteric lymph nodes alters the ratio of B cells to CD8 + T cells in a dose-dependent manner, compromising mucosal immune homeostasis and anti-tumor responses [ 152 ]. Beyond immune regulation, MPs significantly influence TME remodeling by driving metabolic reprogramming and disrupting the gut microbiome. At both the systemic and cellular levels, MPs systemically dysregulate host metabolic homeostasis, upregulating transcription factors such as hypoxia-inducible factor 1-alpha (HIF-1α) and cellular Myc (c-Myc) [ 153 , 154 ], enhancing tumor cell glycolysis and inhibiting fatty acid β-oxidation [ 155 , 156 ], resulting in elevated lactate levels in the TME and abnormal lipid accumulation in the liver. This disrupts mitochondrial energy metabolism in immune cells, inducing tumor drug resistance [ 157 ], and promotes tumor invasion and metastasis via G protein-coupled receptor (GPCR) signaling [ 158 ]. On the other hand, within the local intestinal milieu, this acidic microenvironment acts in concert with reduced MUC2 mucin and dysregulated amino acid metabolism [ 159 – 161 ] to collectively compromise intestinal barrier integrity and elevate the risk of colorectal cancer [ 162 , 163 ]. Importantly, MPs exposure closely links systemic metabolic reprogramming with local microecological disturbances via the microbial-host metabolic axis. At the microbiota level, MPs and NPs contribute to a reduction in beneficial bacteria, an increase in pathogenic bacteria, and a decrease in short-chain fatty acid (SCFA) production [ 159 , 164 – 166 ], disrupting gut immune balance [ 100 , 167 ]. A bidirectional malignant interaction exists between host metabolism and microbiota dysbiosis: the reduction in SCFAs caused by MPs attenuates their anti-inflammatory and metabolic regulatory effects on the host intestinal epithelium [ 168 ]. Concurrently, lactic acid accumulation in the gut epithelium promotes the selection of acid-resistant pathogenic bacteria, exacerbating microbiota imbalance and driving the gut microenvironment toward a pro-cancerous state. Simultaneously, MPs affect the physical matrix architecture of the TME. Transforming growth factor-beta, an MPs-associated inflammatory factor, activates tumor-associated fibroblasts. This promotes extracellular matrix deposition and tissue fibrosis, physically restricting immune cell infiltration and supporting tumor proliferation [ 169 , 170 ], supporting cancer cell proliferation and angiogenesis [ 171 ]. Moreover, NPs-induced vascular endothelial growth factor stimulates dysfunctional neovasculature formation, exacerbating tumor hypoxia and establishing a pro-cancer feedback loop [ 172 , 173 ]. In summary, MPs disrupt immune homeostasis, reprogram metabolic pathways, disrupt the gut microbiome, and activate matrix cells, forming a multi-mechanism synergistic network that drives the TME toward a pro-tumorigenic state. Nevertheless, most current studies are limited to short-term exposure and isolated mechanisms. Future research should integrate immune-metabolic-microbiome-matrix interactions to explore the dynamic processes of TME remodeling by MPs across diverse tumor types and stages. Furthermore, it is essential to investigate intervention strategies targeting MPs-related TME characteristics. Specifically, combining human cohort studies with multi-omics technologies is crucial to systematically uncover how MPs disrupt the human microbiome-metabolome axis and delineate their precise roles in oncogenesis. The persistent MPs-induced inflammatory response is a critical factor in disrupting tissue repair mechanisms and driving the fibrosis process. In this pathological process, MPs drive the tissue microenvironment away from physiological repair and toward pathological fibrosis via immune-metabolic reprogramming, thereby establishing a pro-tumorigenic foundation. Studies suggest a potential link between MPs exposure and the onset of hepatic steatosis, fibrosis, and liver cancer [ 174 , 175 ]. On the one hand, the rigid matrix generated during fibrosis activates integrin-focal adhesion kinase (FAK) signaling, which directly promotes tumor cell proliferation [ 176 ]. On the other hand, the infiltration of immunosuppressive cells and the development of vascular abnormalities within fibrotic tissues collectively create a tumor-supportive microenvironment [ 177 , 178 ]. These factors physically limit cytotoxic T cell infiltration and promote their functional inactivation, thereby facilitating tumor immune evasion. Simultaneously, MPs-induced chronic inflammation and fibrosis interact synergistically, pushing the microenvironment toward a pro-cancerous state. In this context, sustained inflammatory factors such as IL-6 and TNF-α directly stimulate tumor cell proliferation, migration, and invasion [ 102 – 105 ]. Additionally, fibrosis-induced matrix stiffening enhances tumor growth via integrin-FAK signaling and further restricts immune cell infiltration, promoting immune escape. Upon entry into the human body, MPs potentially elicit wide-ranging biological responses, including DNA damage, increased composite toxicity, metabolic reprogramming, and microbial dysbiosis, collectively contributing to tumor initiation and progression (Fig.  3 ). These responses are critical in fostering tumor-associated immunosuppression and may promote carcinogenesis. Mechanistically, these effects are mediated through the upregulation of inflammatory cytokines and the activation of key signaling pathways, which reinforce pro-tumor inflammatory and immune processes at the molecular level. Notably, current evidence linking MPs to carcinogenesis is predominantly derived from cellular and animal models, with human epidemiological data remaining limited. Therefore, further validation through long-term epidemiological cohort studies is warranted. Fig. 3 The multifaceted mechanisms of MPs in tumor initiation and progression. Although MPs possess relatively low intrinsic toxicity, they serve as effective vectors that adsorb and subsequently release organic pollutants, heavy metals, and pathogens—exerting a “Trojan horse” effect that significantly enhances composite toxicity. Their extensive specific surface area and hydrophobic characteristics facilitate the translocation of co-pollutants across biological barriers. These contaminants act synergistically to disrupt signaling pathways, aggravate genomic instability, alter metabolic reprogramming, and induce microecological imbalance. This promotes precancerous lesions in tissues, including the mammary gland, stomach, and colorectum. Moreover, MPs induce gut microbial dysbiosis and host metabolic dysfunction, establishing a self-sustaining vicious cycle that markedly increases cancer risk. The graphical abstract was created using BioRender.com The multifaceted mechanisms of MPs in tumor initiation and progression. Although MPs possess relatively low intrinsic toxicity, they serve as effective vectors that adsorb and subsequently release organic pollutants, heavy metals, and pathogens—exerting a “Trojan horse” effect that significantly enhances composite toxicity. Their extensive specific surface area and hydrophobic characteristics facilitate the translocation of co-pollutants across biological barriers. These contaminants act synergistically to disrupt signaling pathways, aggravate genomic instability, alter metabolic reprogramming, and induce microecological imbalance. This promotes precancerous lesions in tissues, including the mammary gland, stomach, and colorectum. Moreover, MPs induce gut microbial dysbiosis and host metabolic dysfunction, establishing a self-sustaining vicious cycle that markedly increases cancer risk. The graphical abstract was created using BioRender.com In conclusion, existing research yields preliminary evidence for the entire pathological cascade, commencing with physical barrier disruption and progressing through chronic inflammation and fibrosis, ultimately leading to TME formation. However, the detailed interaction mechanisms of various toxic pathways in complex in vivo environments, and the complete causal chain from molecular events to tumorigenesis are yet to be fully elucidated. Future studies should focus on developing complex model systems that mimic real-world exposure conditions, integrating multi-omics and real-time dynamic imaging technologies to comprehensively analyze the interaction networks of toxic pathways. This will provide the scientific basis necessary for a thorough assessment of MPs health risks.

The global surge in plastic production and consumption has led to considerable plastic waste accumulation in the environment. Microplastics (MPs) and nanoplastics (NPs) are generated through physical, chemical, and biological degradation processes [ 1 , 2 ]. MPs are defined as plastic fragments and particles smaller than 5 mm in diameter, while NPs are defined as particles smaller than 100 nm. These particles predominantly arise from primary microplastic produced by the plastic industry and secondary microplastic resulting from the degradation of plastic waste in the environment [ 3 , 4 ]. MPs enter the human body through ingestion via the food chain, inhalation, and skin contact, accumulating in various organs [ 5 , 6 ], which may pose health risks. Although most plastic polymers are biochemically inert, additives such as plasticizers, which enhance flexibility, also increase the persistence of MPs in the environment [ 7 , 8 ]. Consequently, MPs contribute to the widespread contamination of air, soil, and water, acting not only as pollutants but also as carriers of pathogens and environmental toxins, ultimately threatening human health through bioaccumulation [ 9 – 12 ]. Research has identified over 150 plastic additives with carcinogenic properties [ 13 ], underscoring the public health concerns surrounding MPs pollution. At the cellular level, MPs can disrupt cellular equilibrium by causing physical damage, oxidative stress, mitochondrial dysfunction, and DNA damage [ 14 – 16 ]. Long-term genomic damage and chronic inflammation are recognized as primary contributors to tumor formation [ 6 ]. Research indicates that the size, shape, and surface properties of MPs significantly influence their uptake, migration, and toxicity, as well as cycle regulation [ 17 , 18 ]. Recent animal and cell-based studies further suggest that MPs may activate carcinogenic signaling pathways and promote the development of malignant traits, underlining their potential carcinogenic effects [ 19 , 20 ]. While the direct causal relationship between MPs exposure and human cancer requires additional validation, several pivotal studies have provided crucial insights into their potential carcinogenic risks [ 21 , 22 ]. These include the detection of MPs in human tumor samples [ 23 ] and the induction of malignant traits in vitro by MPs [ 24 ]. Accordingly, this review is structured to trace the pathogenic arc of MPs: beginning with their entry into the human body, moving through their tissue distribution and cellular impacts, and culminating in their potential role in tumor initiation and progression (Fig. 1 ). The focus is on the physicochemical toxicity of MPs, their role as pollutant carriers, and their impact on the immune microenvironment. Furthermore, this paper addresses the existing knowledge gaps and challenges in translating research into practical applications, endeavoring to provide a theoretical foundation for understanding the health risks of MPs and developing effective control measures. Fig. 1 From source to disease: human exposure pathways and potential health impacts of MPs. MPs primarily originate from two sources: primary microplastic, which are intentionally manufactured in the plastic industry, and secondary microplastic, formed through the environmental degradation of plastic waste via processes such as solar radiation, mechanical abrasion, and weathering. Owing to their resistance to natural breakdown, MPs exhibit considerable persistence in the environment. Human exposure predominantly occurs through ingestion, inhalation, and dermal contact. MPs have been detected in diverse tissue types, where they can accumulate and exert harmful effects across multiple organ systems—including the respiratory, digestive, and reproductive tracts. Their long-term bioaccumulation poses a potential threat to human health. Following exposure, MPs induce wide-ranging, organ-specific injuries, including reduced lung function, hepatic injury, gut dysbiosis, neurological damage, developmental toxicity, and coagulation disorders. These pathological manifestations are supported by molecular mechanisms such as oxidative stress, DNA damage, and cell cycle dysregulation, which collectively create a tumor-promoting microenvironment and highlight the potential carcinogenic effects of MPs. The graphical abstract was generated using BioRender.com From source to disease: human exposure pathways and potential health impacts of MPs. MPs primarily originate from two sources: primary microplastic, which are intentionally manufactured in the plastic industry, and secondary microplastic, formed through the environmental degradation of plastic waste via processes such as solar radiation, mechanical abrasion, and weathering. Owing to their resistance to natural breakdown, MPs exhibit considerable persistence in the environment. Human exposure predominantly occurs through ingestion, inhalation, and dermal contact. MPs have been detected in diverse tissue types, where they can accumulate and exert harmful effects across multiple organ systems—including the respiratory, digestive, and reproductive tracts. Their long-term bioaccumulation poses a potential threat to human health. Following exposure, MPs induce wide-ranging, organ-specific injuries, including reduced lung function, hepatic injury, gut dysbiosis, neurological damage, developmental toxicity, and coagulation disorders. These pathological manifestations are supported by molecular mechanisms such as oxidative stress, DNA damage, and cell cycle dysregulation, which collectively create a tumor-promoting microenvironment and highlight the potential carcinogenic effects of MPs. The graphical abstract was generated using BioRender.com

The global increase in plastic usage has led to a sharp rise in MPs accumulation in ecosystems. Their presence in human tissues and the associated potential health risks have attracted significant attention. Existing research has identified various toxic effects associated with MPs and NPs, including oxidative stress, genetic damage, inflammation, metabolic disorders, and PCD, all of which suggest a potential link to organ dysfunction and tumorigenesis. However, significant challenges and limitations persist in this field of study. From a methodological standpoint, in vitro experiments often lack standardized parameters such as particle concentration, size distribution, and exposure time, complicating the accurate simulation of complex exposure scenarios in the human body. Moreover, most in vivo studies depend on animal models or retrospective analyses, making it challenging to establish clear causal links. While initial evidence supports an association between MPs and tumor development, the specific pathways through which MPs modulate the TME to promote malignant transformation—particularly the differential biological effects of various types, sizes, and surface characteristics of MPs—have yet to be systematically investigated. Furthermore, most mechanistic evidence currently derives from cell and animal studies, necessitating the validation of actual health effects in humans through large-scale, long-term epidemiological data. In real-world contents, MPs and NPs often serve as carriers for multiple pollutants, and the synergistic or antagonistic toxicity mechanisms of combined exposure remain unclear. To advance current understanding of the relationship between MPs and cancer, a multi-dimensional research approach is urgently required. First, standardized detection and quantification methods for MPs and NPs in human samples should be developed, emphasizing highly sensitive and high-resolution analytical techniques. Second, experimental models should be optimized by creating in vitro simulation systems that closely mimic real-world exposure scenarios, alongside conducting long-term, low-dose exposure animal experiments and human cohort studies. Mechanistically, greater emphasis should be placed on elucidating the interactions and dynamic evolution of different signaling pathways, especially the causal relationship between MPs/NPs-induced metabolic reprogramming and alterations in the immune microenvironment, necessitating further direct experimental evidence. From a risk management perspective, an integrated evaluation framework should be established that combines the inherent toxicity of MPs with their synergistic effects as pollutant carriers. This framework will help limit the use of harmful additives, such as endocrine-disrupting chemicals in plastics, at the source and improve policy systems for managing plastics throughout their entire lifecycle. Although the precise causal relationship between MPs/NPs and cancer remains to be fully elucidated, their stable polymeric structure, high specific surface area, and modifiability offer novel ideas for developing targeted drug delivery systems. Investigating MPs or their biomimetic derivatives as carriers represents a potential direction for transforming an environmental challenge into biomedical innovation; however, their biocompatibility and long-term biosafety must be rigorously evaluated. In summary, this review delineates a conceptual framework linking MPs exposure to carcinogenesis, encompassing key mechanisms including cellular internalization and tissue translocation, the induction of oxidative stress and chronic inflammation, the reprogramming of the TME, and the vector function for co-pollutants, all of which collectively contribute to tumor progression. While current experimental models provide compelling support for this pathway, extrapolating these findings to human cancer risk warrants caution and must account for realistic exposure scenarios, interspecies differences, and the complexity of environmental mixtures. To definitively establish the role of MPs in human carcinogenesis, future studies should integrate environmentally relevant exposure modeling, multi-omics analyses, and large-scale prospective cohorts. These approaches are essential to validate the biological plausibility of this framework and quantitatively determine the disease burden attributable to MPs.

Although MPs exhibit relatively low inherent toxicity, they function as highly effective carriers for environmental pollutants. By adsorbing and gradually releasing organic pollutants, heavy metals, and pathogens, MPs generate a significant “Trojan horse” effect, enhancing the combined toxicity of these complex systems. In synergy with organic pollutants, MPs can adsorb substances like bisphenol A (BPA), maintaining their stability during biological transport and facilitating their passage through biological barriers, thus increasing bioavailability. Once inside the body, BPA mimics estrogen by activating corresponding nuclear receptors and downstream signaling pathways, promoting the abnormal proliferation and migration of breast cells while inhibiting apoptosis, thereby increasing breast cancer risk [ 179 , 180 ]. Furthermore, BPA can enhance ovarian cancer cell stemness via the atypical PTEN-induced kinase 1/p53-mediated mitochondrial (PINK1/p53) autophagy pathway and synergistically upregulate metalloproteinase-2 (MMP2) expression to promote invasion and metastasis [ 181 – 183 ]. These additives reportedly interfere with androgen metabolism and induce abnormal prostate cell proliferation, significantly associated with chemoresistance [ 184 , 185 ]. In interactions with heavy metals, MPs display complex synergistic effects. NPs co-exposed with cadmium produce synergistic toxicity at the mitochondrial level, characterized by decreased membrane potential, increased caspase-3 activity, and calcium homeostasis disruption [ 186 ]. PS-MPs inhibit the function of ATP-binding cassette transporters, suppressing arsenic efflux and promoting its intracellular accumulation, hence amplifying DNA damage and cellular toxicity [ 187 , 188 ]. PE-MPs, in cooperation with cadmium, activate the ATP-P2X7 signaling pathway, accelerating liver fibrosis progression [ 189 – 192 ]. Moreover, MPs serve as carriers for pathogenic microorganisms, forming biofilms on their surfaces that protect Helicobacter pylori , enhancing its ability to colonize the gastric mucosa. This combined damage to the gastric barrier markedly increases the risk of gastric cancer [ 106 ]. MPs also prolong the survival time of viruses and pathogens in the environment, promoting their spread and presenting a compound biological threat to human health [ 193 – 195 ]. Notably, in real-world environments, MPs typically adsorb multiple pollutants concomitantly, potentially exerting even more complex synergistic effects. The carrier efficiency of MPs is dramatically influenced by factors such as particle size, surface charge, and environmental aging. Smaller-sized MPs with larger surface areas, along with those subjected to environmental aging, exhibit stronger adsorption capabilities owing to rougher surfaces and more oxygen-containing functional groups [ 196 , 197 ]. This further emphasizes the critical role of MPs-pollutant composite exposure in driving cancer initiation and progression. Given that most current evidence emanates from studies focused on single pollutants, future research should explore the synergistic mechanisms of complex pollution in real-world environments. It is essential to systematically analyze the carrier behavior of MPs at different stages of environmental aging, as well as their interactions with pollutants, and establish an ecological and health risk assessment framework incorporating the characteristics of composite exposure.