Micro(Nano)plastics in Human Carcinogenesis: Emerging Evidence and Mechanistic Insights

Abstract

Micro(nano)plastics (MNPs) are globally ubiquitous environmental pollutants that have become a growing concern for human health, but their potential role in human carcinogenesis remains to be determined. Over the past few years, MNPs have been identified as potential carcinogenic and mutagenic agents in various human samples as they induce oxidative stress, DNA damage, and immune dysregulation, which can alter the tumor microenvironment, thereby promoting cancer development and metastasis. Researchers are actively investigating the health risks posed by MNP particles in order to establish clearer links between MNP exposure and the onset of various human cancers. Although recent research suggests a potential tumorigenic connection between MNPs and some cancer types like skin, lung, breast and gastrointestinal cancers, further studies are required to clarify their long-term effects and specific mechanisms. In our review, we provide an overview of the current state of knowledge regarding the carcinogenic impacts of MNPs and the underlying molecular mechanisms through which MNP exposure may contribute to human cancer progression. Additionally, we highlight existing knowledge gaps and provide important recommendations for future research on the carcinogenic potential of MNPs.

1. Introduction

Plastics have emerged as a significant environmental pollutant in the 21st century due to their widespread use and ubiquitous nature. To date, micro(nano)plastics (MNPs) are an emerging challenge globally as well as a significant health concern [1,2]. Global plastic consumption was estimated at 460 million tons in 2019 and is projected to reach an alarming 1231 million tons by 2060 [3]. Through degradation and fragmentation, larger plastic materials break down into microplastics (MPs; <5 mm) and nanoplastics (NPs; <100 nm), collectively referred to as MNPs [4,5]. These particles are now ubiquitous in terrestrial, aquatic, and atmospheric systems, making human exposure inevitable through ingestion, inhalation, and dermal contact, which is leading to multiple deleterious health effects [4,5,6,7]. Given their pervasiveness and potential risks to both the environment and human health, MNPs have become a global issue. As a result, there is an urgent need for researchers or scientists to further investigate their origins, characteristics, ecological impacts, and health-related consequences. Due to their small size and persistent nature, MNPs can easily cross biological barriers and accumulate in various organs, including the lungs, liver, colon, kidneys, and potentially the brain [5]. This has been substantiated by the detection of MNPs in human samples, such as blood, placenta, saliva, feces, breast milk, and urine, raising significant concerns about their impact on human health [8,9]. Several studies have also found MNPs in tissue samples of various types of human tumors, as illustrated in Table 1. Comparative analyses of normal and tumor tissues have revealed a higher proportion of MNPs in tumor samples, raising serious concerns (Table 2). Moreover, MNPs can carry toxic additives, heavy metals, and environmental pollutants adsorbed onto their surfaces, further exacerbating their potential toxicity, and these have been linked to increased carcinogenic risk [6,10,11]. With the increasing global exposure to MNPs, it is crucial to evaluate the potential human cancer risks associated with MNPs and their additives. These additives have been found to interfere with key biological pathways such as metabolism and hormonal (endocrine) signaling [12].

Over the past few years, growing concern over MNP pollution has resulted in a rapid increase in research in this area. To illustrate this trend, we performed a bibliometric analysis using the Scopus database, which also revealed an exponential increase in the number of publications related to MNPs and cancer (Figure 1). Despite the growing awareness and increased research on MNPs, there is a lack of comprehensive data on their role in cancer progression and development. While prolonged exposure to MNPs has been strongly linked to the development of cancer in both animals and humans [13], relatively few studies have directly assessed the carcinogenic potential of MNPs. Thus, this review aims to critically examine the current state of knowledge regarding microplastic exposure and its association with cancer development. We explore the underlying molecular mechanisms through which MNPs may contribute to carcinogenesis, emphasizing findings that directly demonstrate their carcinogenic potential. Additionally, we provide recommendations to guide future research efforts in evaluating the carcinogenic impacts of MNPs.

Table 1. Micro(nano)plastics detected in human tumor samples.

Type of Cancer/Sample	Type of Microplastic Detected	Size/Concentration of Microplastic	Detection Technique	Reference
Cervical cancer (tumor tissue)	PE, PP	<20 µm 2.24 ± 1.61 MP particles/g	Micro-Raman spectroscopy Scanning electron microscopy	[14]
Cervical cancer (blood, tumor tissue, and paracancerous tissue)	PE, PP	Blood: 2.2 ± 1.42 MP particles/mL Tumor: 1.67 ± 0.94 MP particles/mL) Paracancer: 0.87 ± 0.72 MP particles/mL	Raman spectroscopy Pyrolysis–gas chromatography–mass spectroscopy (Py-GC/MS)	[15]
Prostate cancer (paratumor and tumor tissue)	PS, PE, PP, PVC	Paratumor: 20–30 µm 181.0 µg/g Tumor: 50–100 µm 290.3 µg/g	Pyrolysis–gas chromatography–mass spectroscopy (Py-GC/MS)	[16]
Breast cancer (tumor tissue)	PIC, PP	>100 µm	Laser direct infrared (LDIR) spectroscopy Scanning electron microscopy (SEM)	[17]
Lung cancer Pancreatic cancer Gastric cancer Colorectal cancer Cervical cancer (tumor tissue)	PS, PVC, PE	111.04 ± 156.77 ng MP/g	Pyrolysis–gas chromatography–mass spectroscopy (Py-GC/MS)	[18]
Colorectal cancer (colon resection samples)	PE, PMMA, PA	1–613 µm 702.68 ± 504.26 MP particles/g	Attenuated total reflection–Fourier-transform infrared (ATR-FTIR) spectroscopy Raman spectroscopy	[19]
Colorectal cancer (tumor tissues)	PP, PE, PA, PET, PVC	20–500 µm	Laser direct infrared (LDIR) chemical imaging system Scanning electron microscopy (SEM)	[20]
Colorectal cancer (tumor and peritumoral tissues)	PA, PET, PVC, PU	<100 µm	Laser direct infrared (LDIR) chemical imaging system Scanning electron microscopy (SEM)	[21]
Penile cancer (cancerous and paracancerous tissues)	PE, PP, PVC, PA	20–50 µm	Laser direct infrared (LDIR) spectroscopy	[22]

Abbreviations: PA—polyamide; PE—polyethylene; PET—polyethylene terephthalate; PIC—chlorinated polyisoprene; PMMA—poly(methyl methacrylate); PP—polypropylene; PS—polystyrene; PU—polyurethane; PVC—polyvinyl chloride.

Table 1. Micro(nano)plastics detected in human tumor samples.

Type of Cancer/Sample	Type of Microplastic Detected	Size/Concentration of Microplastic	Detection Technique	Reference
Cervical cancer (tumor tissue)	PE, PP	<20 µm 2.24 ± 1.61 MP particles/g	Micro-Raman spectroscopy Scanning electron microscopy	[14]
Cervical cancer (blood, tumor tissue, and paracancerous tissue)	PE, PP	Blood: 2.2 ± 1.42 MP particles/mL Tumor: 1.67 ± 0.94 MP particles/mL) Paracancer: 0.87 ± 0.72 MP particles/mL	Raman spectroscopy Pyrolysis–gas chromatography–mass spectroscopy (Py-GC/MS)	[15]
Prostate cancer (paratumor and tumor tissue)	PS, PE, PP, PVC	Paratumor: 20–30 µm 181.0 µg/g Tumor: 50–100 µm 290.3 µg/g	Pyrolysis–gas chromatography–mass spectroscopy (Py-GC/MS)	[16]
Breast cancer (tumor tissue)	PIC, PP	>100 µm	Laser direct infrared (LDIR) spectroscopy Scanning electron microscopy (SEM)	[17]
Lung cancer Pancreatic cancer Gastric cancer Colorectal cancer Cervical cancer (tumor tissue)	PS, PVC, PE	111.04 ± 156.77 ng MP/g	Pyrolysis–gas chromatography–mass spectroscopy (Py-GC/MS)	[18]
Colorectal cancer (colon resection samples)	PE, PMMA, PA	1–613 µm 702.68 ± 504.26 MP particles/g	Attenuated total reflection–Fourier-transform infrared (ATR-FTIR) spectroscopy Raman spectroscopy	[19]
Colorectal cancer (tumor tissues)	PP, PE, PA, PET, PVC	20–500 µm	Laser direct infrared (LDIR) chemical imaging system Scanning electron microscopy (SEM)	[20]
Colorectal cancer (tumor and peritumoral tissues)	PA, PET, PVC, PU	<100 µm	Laser direct infrared (LDIR) chemical imaging system Scanning electron microscopy (SEM)	[21]
Penile cancer (cancerous and paracancerous tissues)	PE, PP, PVC, PA	20–50 µm	Laser direct infrared (LDIR) spectroscopy	[22]

Abbreviations: PA—polyamide; PE—polyethylene; PET—polyethylene terephthalate; PIC—chlorinated polyisoprene; PMMA—poly(methyl methacrylate); PP—polypropylene; PS—polystyrene; PU—polyurethane; PVC—polyvinyl chloride.

Table 2. Comparative analysis of the abundance of micro(nano)plastics in normal human samples and in tumor samples.

Normal Tissue Sample	Type/Size/Concentration of Microplastic Detected	Tumor Sample	Type/Size/Concentration of Microplastic Detected	References
Prostate tissue	PA, PP, PAA, PDMS (2.5–26 µm)	Prostate cancer	PS, PE, PP, PVC (50–100 µm; 290.3 µg/g)	[16,23]
Breast milk	PE, PVC, PP (2–12 µm)	Breast cancer	PIC, PP (>100 µm)	[17,24]
Lung tissue	PP, PET (12–2475 μm; 0.69 ± 0.84 MP particles/g	Lung cancer	PS, PVC, PE (122.30 ± 154.88 ng/g)	[18,25]
Colon tissue (colectomy samples)	PC, PA, PP (800–16,000 µm; 28.1–15.4 MP particles/g)	Colorectal cancer (colon resection samples)	PE, PMMA, PA (1–613 µm 702.68 ± 504.26 MP particles/g)	[19,26]
Penile tissue	PET, PP (20–500 µm)	Penile cancer (cancerous and paracancerous tissues)	PE, PP, PVC, PA (20–50 µm)	[22,27]
Kidney (nephrectomy samples)	PE, PS (1–29 µm)	Clear-cell renal-cell carcinoma (tumor tissue)	PET, PVC (<200 µm)	[28,29]

Abbreviations: PA—polyamide; PAA—polyacrylic acid; PC—polycarbonate; PDMS—poly(dimethylsiloxane); PE—polyethylene; PET—polyethylene terephthalate; PIC—chlorinated polyisoprene; PMMA—poly(methyl methacrylate); PP—polypropylene; PS—polystyrene; PVC—polyvinyl chloride.

Table 2. Comparative analysis of the abundance of micro(nano)plastics in normal human samples and in tumor samples.

Normal Tissue Sample	Type/Size/Concentration of Microplastic Detected	Tumor Sample	Type/Size/Concentration of Microplastic Detected	References
Prostate tissue	PA, PP, PAA, PDMS (2.5–26 µm)	Prostate cancer	PS, PE, PP, PVC (50–100 µm; 290.3 µg/g)	[16,23]
Breast milk	PE, PVC, PP (2–12 µm)	Breast cancer	PIC, PP (>100 µm)	[17,24]
Lung tissue	PP, PET (12–2475 μm; 0.69 ± 0.84 MP particles/g	Lung cancer	PS, PVC, PE (122.30 ± 154.88 ng/g)	[18,25]
Colon tissue (colectomy samples)	PC, PA, PP (800–16,000 µm; 28.1–15.4 MP particles/g)	Colorectal cancer (colon resection samples)	PE, PMMA, PA (1–613 µm 702.68 ± 504.26 MP particles/g)	[19,26]
Penile tissue	PET, PP (20–500 µm)	Penile cancer (cancerous and paracancerous tissues)	PE, PP, PVC, PA (20–50 µm)	[22,27]
Kidney (nephrectomy samples)	PE, PS (1–29 µm)	Clear-cell renal-cell carcinoma (tumor tissue)	PET, PVC (<200 µm)	[28,29]

Abbreviations: PA—polyamide; PAA—polyacrylic acid; PC—polycarbonate; PDMS—poly(dimethylsiloxane); PE—polyethylene; PET—polyethylene terephthalate; PIC—chlorinated polyisoprene; PMMA—poly(methyl methacrylate); PP—polypropylene; PS—polystyrene; PVC—polyvinyl chloride.

Figure 1. Global publication trend for micro/nanoplastics (MNPs) and its connection with cancer in the Scopus database, 2010–2026. Annual number of documents published worldwide on the topic of micro/nanoplastics (A) and micro/nanoplastics in cancer (B) retrieved from the Scopus database on 24 August 2025. The trend shows an exponential increase in publications since 2018. The data were obtained using the search query “microplastics or nanoplastics” (A) and “microplastics or nanoplastics, and cancer” (B). Obtained from the Scopus database.

Figure 1. Global publication trend for micro/nanoplastics (MNPs) and its connection with cancer in the Scopus database, 2010–2026. Annual number of documents published worldwide on the topic of micro/nanoplastics (A) and micro/nanoplastics in cancer (B) retrieved from the Scopus database on 24 August 2025. The trend shows an exponential increase in publications since 2018. The data were obtained using the search query “microplastics or nanoplastics” (A) and “microplastics or nanoplastics, and cancer” (B). Obtained from the Scopus database.

2. Review Methodology

This narrative review was conducted based on a comprehensive literature search using PubMed and Google Scholar. The search strategy employed the keywords “microplastics”, “nanoplastics”, “plastic additives”, “DNA damage”, “genotoxic”, “immunotoxic”, “synergistic”, “combined toxicity”, “carcinogenic”, “tumorigenic”, “cancer”, “tumor”, and “therapy resistance”, applied individually or in combination. Publications from 2010 to 2025 were screened, retrieved, and critically evaluated, and relevant information was extracted and synthesized for the preparation of this manuscript.

3. Molecular Mechanism of Micro(Nanoplastic)-Induced Carcinogenesis

Carcinogenesis is a multistep process driven by genetic, epigenetic, and microenvironmental alterations that drive the transformation of normal cells into malignant phenotypes. An increasing number of studies have linked MNPs to the development of multiple types of cancer (Figure 2). After exposure to MNPs, cells take up MNP particles via clathrin- or caveolae-mediated endocytosis, macropinocytosis, passive membrane penetration, and paracellular diffusion, leading to cellular damage and disruption of cellular homeostasis [10,11,12,13,30]. This results in activation of multiple signaling pathways, damaged cellular organelles, inflammation, DNA damage, and, ultimately, mutations that alter cellular growth, potentially favoring cancer initiation and progression, as shown in Figure 3. Some of the possible mechanisms of MNP-induced carcinogenesis are discussed in the following sections.

3.1. Oxidative Stress as a Driver of Carcinogenesis

Oxidative stress is a primary molecular mechanism driving carcinogenesis and a key pathway through which MNPs exert toxicity. MNP exposure has been shown to induce excessive production of reactive oxygen species (ROS), overcoming endogenous antioxidant systems like superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPx). Elevated intracellular ROS levels affect antioxidant defenses, including SOD, catalase, and GPx, suggesting the redox balance has shifted towards a pro-oxidant state. This oxidative imbalance leads to lipid peroxidation, protein oxidation, and nucleic acid modifications, directly compromising genomic integrity [9,31,32,33,34]. For instance, the accumulation of 8-hydroxy-2′-deoxyguanosine (8-oxo-dG) results in a mutagenic lesion frequently observed under ROS stress and associated with GC → TA transversions in oncogenes and tumor suppressor genes [33,34].

Persistent oxidative stress not only causes mutagenesis but also aberrantly activates receptor tyrosine kinases (RTKs) such as epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR), and insulin-like growth factor receptor (IGF-1R). Dysregulation of these pathways is central to cancer development and progression [35,36]. Importantly, exposure to MNPs has been shown to generate oxidative stress, which can directly or indirectly activate RTKs. In turn, this may promote multiple downstream oncogenic signaling cascades, including mitogen-activated protein kinase/extracellular signal-related kinase (MAPK/ERK), c-Jun N-terminal kinase (JNK), p38 kinase, nuclear factor erythroid 2-related factor 2 (Nrf2), phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt), Wnt/β-catenin, and NF-κB pathways, thereby linking oxidative stress to carcinogenesis [9,32,37]. In vitro models have shown that polystyrene MNPs induce mitochondrial depolarization, increase ROS accumulation, and impair mitochondrial respiration, which are classical hallmarks of oxidative stress-driven carcinogenesis [38]. Importantly, oxidative stress acts in synergy with other carcinogenic pathways: it enhances chronic inflammation by activating redox-sensitive transcription factors like NF-κB and AP-1 while simultaneously interfering with DNA repair pathways and amplifying genomic instability, which is a hallmark of cancer [39,40]. Collectively, oxidative stress induced by MNP exposure represents a central initiating event that serves as a bridge between environmental plastic contamination and carcinogenic transformation in human tissues.

A study on human epidermoid carcinoma cell line (A431) co-exposed to polystyrene nanoplastics (PS-NPs; 44.9 ± 10.5 nm; 10–500 µg/mL) and EGF (100 ng/mL) showed that EGF increased the uptake of PS-NPs in A431 cells via clathrin-mediated endocytosis [41]. In another study, zebrafish embryos exposed to PS-NPs (20 nm; 2–8 mg/L) demonstrated morphological and vascular distortions, which were mediated by the VEGFA/VEGFR signaling pathway, together with a significant increase in mRNA expression levels of VEGFA, NRP1, and KlF6a [42]. Ding and colleagues reported that long-term oral exposure to PS-MPs (5 mg/L for 90 days) in rats resulted in their wide distribution in tissues, with a greater concentration in gastric tissues, together with a significant increase in ROS levels, reduced activity of antioxidant enzymes (superoxide dismutase, SOD; glutathione peroxidase, GSH-Px; catalase, CAT), elevated lipid peroxidation (malondialdehyde, MDA), and increased oxidative DNA damage (8-oxo-dG; phosphorylated histone H2AX, γ-H2AX). Additionally, the oxidative damage of tissues was observed in a size-dependent manner, i.e., the smaller the size, the greater the toxicity [43]. Moreover, the increased oxidative stress and damage were also shown to be correlated in an in vitro study using human gastric epithelial cells (GES-1) at a concentration of 50 µg/mL. An immunofluorescence study demonstrated that PS-MPs induced oxidative damage through upregulation of the β-catenin/YAP signaling pathway, which is a key regulator in various types of cancer [43]. Jiang and colleagues observed mitochondrial damage, ROS generation, and reduced activity of antioxidant enzymes upon treatment of polyester microplastic fibers (PET-MFs; 0, 50, 500 MFs/mL) with newly hatched Daphnia carinata (a planktonic crustacean) [44]. Additionally, a high concentration of PET-MFs (500 MFs/mL) resulted in greater mortality of D. carianata, while increased oxidative stress, mitochondrial damage, and apoptosis were evident, even at a lower concentration (50 MFs/mL). Moreover, a study on female juvenile mice exposed to PS-MPs (1 µm; 0, 0.5, 2 mg/kg) for 28 days demonstrated a substantial increase in oxidative stress in ovaries, as indicated by downregulation of antioxidant enzymes and increasing MDA levels [45]. Molecular analysis revealed activation of the PERK-eIF2α-ATF4-CHOP signaling cascade, indicating endoplasmic reticulum stress, apoptosis, and ovarian toxicity that was reversed upon treatment with N-acetyl-cysteine (ROS inhibitor) and salubrinal (eIF2α dephosphorylation blocker). These findings clearly demonstrate that MP-induced oxidative damage can alter key signaling pathways, potentially leading to carcinogenesis.

3.2. DNA Damage and Genotoxicity

A critical step in human carcinogenesis is the induction of DNA damage and subsequent genomic instability, and there is increasing evidence that MNPs can act as genotoxic agents. MNPs have been shown to induce DNA mutations and damage, which may lead to tumor initiation and progression (Figure 3) [5,46,47]. MNP-induced ROS plays a central role here, as oxidative radicals produce DNA base modifications, DNA strand breaks, chromosomal aberrations, oxidatively damaged DNA, oxidative-induced lesions, and DNA–DNA or DNA–protein adducts [9,47,48]. Persistent damage overcomes DNA repair machinery such as base excision repair (BER), mismatch repair (MMR), and nucleotide excision repair (NER), resulting in the accumulation of mutations in key cancer-related genes [33,49]. Moreover, MNPs may act as vectors that carry and release carcinogenic additives (such as bisphenol A, phthalates, and heavy metals) into cells, thereby compounding DNA damage [50,51]. Such associated chemicals can form bulky DNA adducts that are either mis-repaired or bypassed by translesion synthesis polymerases, introducing mutations. The cumulative result is an increased mutation burden that drives oncogene activation (KRAS, MYC) and tumor suppressor inactivation (TP53, BRCA1) [52,53]. Importantly, genotoxic effects of MNPs are not limited to direct DNA interactions; they also disrupt mitotic spindle formation, leading to aneuploidy and chromosomal instability, which are recognized hallmarks of cancer [54,55].

Møller and Roursgaard indicated that modified PS particles in high concentrations are genotoxic, with immune cells being more prone than other cells, which may be due to greater internalization of PS particles [47]. Moreover, the study highlighted that exposure to PS particles resulted in increased DNA strand breaks in leukocytes and prefrontal cortex cells in animal studies [47]. Another in vitro study on human peripheral blood mononuclear cells (PBMCs) compared the genotoxic potential of 29, 44, and 72 nm PS-NPs at concentrations of 0.0001 to 100 µg/mL for 24 h [56]. The results demonstrated that the smallest NPs (29 nm) at 10 and 100 µg/mL concentrations caused the highest double-DNA-strand breaks, while the largest NPs (72 nm) did not cause any lesions. Additionally, the observed DNA damage was completely repaired after 120 min with the 44 and 72 nm NPs, while there was no complete DNA repair for the smallest NPs. Oxidative DNA damage was also observed with a 0.01 µg/mL concentration of the smallest NPs (29 nm), while the larger particles (44 and 72 nm) required a higher concentration to elicit the same response. The study clearly indicated that smaller-sized PS-NPs were more genotoxic, which may be attributed to their easier permeability into the cells. As with in vitro studies, animal studies have also exhibited the genotoxic potential of MNPs. Farag and colleagues have demonstrated that upon the oral administration of polyethylene microplastics (PE-MPs; 4–6 µM) at varying concentrations (3.75 mg/kg, 15 mg/kg, or 60 mg/kg) to adult rats for 35 days, there was a dose-dependent increase in DNA damage, as well as increased DNA methylation [57]. Similarly, Mai et al. found that when mussels (Mytilus galloprovincialis) were exposed to spherical PE particles (27–32 μm) and fibrous polyethylene terephthalate (PET; 200–400 μm) particles, there was a rise in DNA fragmentation in gill cells, which was dependent on both dose and time, as indicated by the TUNEL assay [58]. Together, these findings strongly implicate DNA damage and genotoxicity as key molecular links between MNP exposure and human carcinogenesis.

3.3. Chronic Inflammation and Immune Dysregulation

Chronic inflammation represents another cornerstone in the molecular mechanism of carcinogenesis, which plays a central role in tumor initiation and progression, and MNPs are emerging as potential inflammatory stimuli within human tissues. Recent evidence indicates that MNPs can induce persistent immune activation [59]. Immune cells (macrophages, dendritic cells), upon exposure to MPs, take up the MNP particles, resulting in the production of danger-associated molecular patterns (DAMPs), which can activate pattern recognition receptors (PRRs) like Toll-like receptors (TLRs) and NOD-like receptors (NLRs), leading to the activation of pro-inflammatory transcription factors including NF-κB and AP-1 [60,61]. This activation drives the production of inflammatory cytokines such as IL-1β, IL-6, and TNF-α, which create a tumor-promoting microenvironment by enhancing cell proliferation, suppressing apoptosis, and promoting angiogenesis, as illustrated in Figure 3 [60,61]. MNP-induced mitochondrial dysfunction and ROS accumulation also activate the NLRP3 inflammasome, resulting in caspase-1-mediated maturation of IL-1β and IL-18, further triggering chronic inflammation [62]. Furthermore, this sustained inflammatory context promotes DNA damage through the release of nitric oxide and ROS by activated immune cells [63]. Prolonged inflammatory signaling skews the balance towards immunosuppression by inducing myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), and exhausted cytotoxic T cells, thereby impairing effective antitumor immunity [64,65].

A study on RAW 264.7 cells showed that treatment with 500 nm PE-NPs at 20 µg/mL for 12 h led to increased expression of Galectin-3 and lysosome-associated membrane protein 1 (LAMP1) and elevated levels of programmed death-ligand 1 (PD-L1) and CD80 expression, along with interleukin-1β (IL-1β) release, suggesting the induction of macrophage inflammation. In parallel, in vivo studies on mice exposed to PE-NPs and PS-NPs (10 mg/kg) for one week revealed a significant upregulation of CD45⁺ and CD80⁺ F4/80⁺ cells (pro-inflammatory macrophages) in Payer’s patches, an increased proportion of IL-1β-producing macrophages, and upregulation of Ctsb, Lamp1, ll1b, and PD-L1 expression in the colon, which further signifies lysosomal damage. Moreover, the study also observed increased differentiation of Treg and T helper 17 (Th17) cells, suggesting T-cell exhaustion. The researchers concluded that NPs disrupt the colonic microenvironment, promoting conditions that favor tumor initiation and progression [66]. High expression of immune checkpoint proteins, such as PD-L1, is associated with downregulation of antitumor immune response, which promotes tumor growth and metastasis [67]. Kim et al. demonstrated that treating gastric cancer cell lines (AGS, MKN1, MKN45, NCI-N87, and KATOIII) with PS-MPs (8.61 × 10⁵ particles/mL for 4 weeks) resulted in an increased PD-L1 expression in all the tested cell lines [68]. A 4.23-fold overall increase in PD-L1 expression was observed across the tumor cells, which was accompanied by increased cellular proliferation and migration in all the tested cell lines. Moreover, oral administration of PS-MPs (1.72 × 10⁴ particles/mL for 4 weeks) in the NCI-N87 xenograft mouse model resulted in accumulation of microplastic particles in the gastric tissue. Notably, increased PD-L1 expression was also observed in the xenograft mouse tissue at both the gene and protein levels. Together, these findings suggest that MNP-induced chronic inflammation and immune dysregulation constitute a potent driver of tumor initiation and progression.

3.4. Epigenetic Reprogramming and Gene Expression Alterations

Epigenetic dysregulation represents a fundamental mechanism of carcinogenesis, bridging environmental exposures to heritable changes in gene expression without altering the DNA sequence [69]. Increasing evidence suggests that MNPs can modulate epigenetic regulators, thereby reshaping transcriptional programs linked to tumor initiation and progression [70]. Epigenetic reprogramming includes DNA methylation, histone modifications, and non-coding RNA regulation, all of which are critical for maintaining genomic stability and proper gene expression [71]. Previous studies have shown that exposure to plastic-derived chemicals, such as bisphenol A (BPA) and phthalates leached from MNPs, induces global hypomethylation and promoter-specific hypermethylation of tumor suppressor genes such as p16INK4a, BRCA1, and TP53 [72]. Such methylation imbalances promote chromosomal instability while silencing critical DNA repair and cell cycle regulators. Additionally, MNP exposure has been associated with altered histone acetylation and methylation patterns that favor open chromatin conformation at oncogenic loci [73]. Beyond DNA and histone modifications, MNPs exert regulatory effects through microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). For example, oxidative stress induced by NP exposure alters the expression of oncogenic miRNAs (miR-21, miR-155) while suppressing tumor-suppressive ones (miR-34, let-7 family), thereby shifting the balance toward cell survival, proliferation, and resistance to apoptosis [74,75,76]. This epigenetic remodeling has downstream consequences on signaling pathways such as PI3K/AKT, MAPK, and TGF-β, all strongly implicated in tumorigenesis. Emerging in vivo models provide further mechanistic insights. Zebrafish exposed to NPs demonstrated transgenerational epigenetic inheritance, with altered methylation landscapes and dysregulated expression of genes linked to developmental and cancer pathways [77,78]. These findings highlight that MNP-induced epigenetic alterations are not only immediate but may persist across generations, amplifying cancer risk in exposed populations. Collectively, MNP-induced epigenetic reprogramming provides a plausible mechanism linking environmental plastic exposure to long-term carcinogenic risk.

3.5. MNPs as Vectors for Carcinogens and Co-Exposure Synergy

Another critical mechanism by which MNPs may contribute to carcinogenesis is through acting as vectors for carcinogenic compounds and facilitating co-exposure synergy. MNPs are highly hydrophobic and possess large surface areas, enabling them to adsorb and concentrate persistent organic pollutants (POPs), heavy metals, polycyclic aromatic hydrocarbons (PAHs), and other toxicants from the environment. Upon ingestion or inhalation, these MNP-bound contaminants are released into human tissues, dramatically enhancing their bioavailability and toxic potential [1,79]. Experimental studies have shown that PS-NPs can adsorb benzo[a]pyrene (BaP), a potent carcinogen, and facilitate its intracellular delivery, where BaP induces bulky DNA adducts and mutagenesis [80]. Similarly, phthalates and bisphenols filtered from plastics have endocrine-disrupting and genotoxic effects, including estrogen receptor activation, oxidative DNA damage, and disruption of cell cycle checkpoints [12,81,82]. The co-transport of these carcinogens amplifies the direct genotoxic and epigenotoxic effects of MNPs themselves. Importantly, the “Trojan horse effect” of MNPs means that even otherwise low-dose carcinogen exposures may be biologically significant when concentrated and transported by plastics. Furthermore, co-exposure synergy between MNPs and chemical contaminants enhances pro-carcinogenic processes such as ROS generation, DNA damage, and chronic inflammation [51,83,84].

Santovito et al. reported that exposing human lymphocytes to a combination of PS-MPs (1 µm; 200 µg/mL) and BPA (0.100 µg/mL) significantly increased the frequency of micronuclei and nuclear buds, indicating an augmented genotoxic effect greater than either contaminant alone [51]. Similarly, an in vitro study on HepG2 cells demonstrated that co-exposure to PS-MPs/NPs (1 µm and 70 nm; 50 μg/mL) and triphenyl phosphate (TPHP, a plasticizer and flame retardant; 10–200 nmol/L) resulted in greater oxidative stress, mitochondrial membrane disruption, and apoptotic changes than TPHP alone, suggesting increased hepatic toxicity and carcinogenic potential [83]. Notably, the study found a greater combined toxicity with PS-NPs compared to PS-MPs, which was attributed to their smaller size, allowing for easier cellular penetration and delivery of TPHP into the cytoplasm. Co-exposure of Caenorhabditis elegans (a free-living nematode) to PS-NPs (80 nm; 10 μg/L) and benzo[a]pyrene (a PAH; 20 μg/L) synergistically increased ROS levels and mitochondrial dysfunction, ultimately reducing the lifespan of the nematodes [80]. The authors attributed this to dysregulated glutathione metabolism and ferroptosis. Similar synergistic effects have been reported with heavy metals. For instance, co-treatment with polyvinyl chloride/polypropylene microplastics (PVC/PP-MPs; 5 µm, 200 µg/L) and cadmium (Cd; 10 µg/L) in zebrafish markedly increased pro-inflammatory markers (IL-1β) and oxidative stress indicators (SOD and MDA) to a greater extent than individual exposure [84]. Furthermore, metabolomic analysis revealed that this synergistic toxicity was linked to dysregulation of amino acid metabolism and gut microbiome dysbiosis, characterized by an increase in abundance of Proteobacteria and Vibrio and a decrease in Gemmobacter. Swathi and colleagues quantified cancer risk using individual Incremental Lifetime Cancer Risk (ILCR) and interaction-based ILCR (ILCR_int) models, revealing a dramatic increase in ILCR_int for adults exposed to diethylhexyl phthalate (DEHP) leached from MPs in combination with heavy metals (ILCR_int of 0.007) compared to DEHP alone (ILCR of 1.77 × 10⁻⁶), underscoring the synergistic enhancement of carcinogenic risk posed by these co-exposures [85]. Additionally, a recent toxicogenomic evaluation of plastic additives through chemical databases has highlighted that more than 150 additives employed in plastic production possess carcinogenic potential, whereas about 90% lack data on carcinogenic endpoints [86]. This further shows a profound knowledge gap regarding the real-world “cocktail effects” of MNPs with diverse additives and emphasizes the necessity for assessing carcinogenicity both at the level of individual additives and within complex mixtures. Therefore, the ability of MNPs to act as mobile carriers for carcinogens represents a critical indirect mechanism of human carcinogenesis, expanding the toxicological significance of plastics far beyond their physical presence. This dual role—as both independent stressors and facilitators of other carcinogens—creates a potent carcinogenic milieu with enhanced risks for tumor initiation and progression.

3.6. Endocrine Disruption and Hormonal Signaling

Endocrine disruption is an increasingly recognized mechanism of carcinogenesis, particularly in hormonally regulated cancers such as breast, ovarian, prostate, and thyroid cancers. MNPs and their leachates, including bisphenol A (BPA), phthalates, and styrene derivatives, are well-characterized endocrine-disrupting chemicals (EDCs) capable of mimicking or antagonizing natural hormones. These interactions occur primarily through estrogen receptors (Erα and ERβ), androgen receptors (ARs), and thyroid hormone receptors, thereby perturbing normal hormonal signaling and creating a pro-carcinogenic environment [12,87]. For instance, BPA exhibits estrogenic activity by binding ERα, inducing proliferative signaling in mammary epithelial cells, and increasing susceptibility to breast carcinogenesis [82]. Likewise, a study on breast cancer cells (MCF-7) demonstrated that BPA can enhance aromatase expression and activity, resulting in increased levels of 17β-estradiol and the proliferation of ERα-positive MCF-7 cells [87]. A higher concentration of BPA in MCF-7 cells was associated with increased ERα expression. Moreover, in the same cell line, BPA exposure resulted in cellular proliferation and increased expression of ERα, pS2, and B-cell lymphoma-2 (Bcl-2) [87]. Comparable findings were observed in animal and xenograft models where BPA exposure resulted in an increased growth of breast cancer cells and metastasis, which was associated with increased expression of Erα, p-Erα, and PKD1 [87].

Similarly, phthalates disrupt androgen receptor signaling, reducing testosterone levels and contributing to prostate carcinogenesis [88]. Additionally, phthalates have been reported to increase the proliferative nature and invasiveness of breast cancer cells (MCF-7 and MDA-MB-231) via the AhR-cAMP-PKA-CREB1 pathway [89]. Interestingly, a cohort study conducted in Denmark showed that women who took medications containing high levels of dibutyl phthalate (DBP) were about twice as likely to develop ER-positive breast cancer [90]. The cumulative endocrine-disrupting effects of MNPs may lead to uncontrolled proliferation, evasion of apoptosis, and increased angiogenesis—hallmarks of cancer development. Additionally, endocrine disruption does not occur in isolation but interacts with oxidative stress and epigenetic mechanisms. For instance, BPA exposure induces ER-mediated DNA methylation changes in breast epithelial cells, linking endocrine disruption with epigenetic reprogramming [91]. Moreover, endocrine-disrupting effects extend to non-genomic signaling pathways, such as PI3K/AKT and MAPK, further accelerating carcinogenic transformation. Animal studies confirm the relevance of MNP-mediated endocrine disruption [87]. Rodents exposed to NPs demonstrated altered serum hormone levels, reproductive abnormalities, and increased incidence of hormone-sensitive tumors [92,93]. These findings emphasize that endocrine disruption mediated by MNPs is a plausible and potent mechanism driving hormone-dependent carcinogenesis in humans.

4. Micro(Nano)plastics as Drivers of Tumor Growth, Metastasis, and Therapy Resistance

Recent investigations have highlighted a strong association between MNPs and carcinogenesis, with emerging evidence suggesting their role in promoting cancer cell proliferation and metastasis (Table 3). Wang and colleagues reported that exposure of PS-MPs (0–1 mg/mL) enhanced proliferation of skin squamous cell carcinoma cell lines (SCL-1 and A431) in a dose- and time-dependent manner, accompanied by increased uptake of MPs, a rise in the proportion of cells in the S and G2 phase, and upregulation of CyclinD1, c-Myc, Bcl-2, and Ki67, suggesting tumor cell proliferation [94]. Molecular analysis revealed elevated mitochondrial ROS levels and NLRP3 inflammasome activation in the cancer cells that contributed to increased inflammatory cytokine levels (TNFα, IL-6, and IL-1β), while NLRP3-mediated inflammation and cell death were observed in normal skin cells (HaCaT). Another study on human glioblastoma cells (U87) treated with PE-MPs (37–75 µM; 0.62–20 mg/mL) demonstrated enhanced proliferation under both acute (72 h) and chronic (26 days) exposure, with a substantial increase in migratory properties and spheroid formation upon chronic exposure to MPs [95]. Similarly, Rafazi et al. reported increased proliferation and spheroid survival in human gastric adenocarcinoma (AGS) cells after PE/PP-MP exposure (37–75 µm; 72 h) in both 2D and 3D models, respectively [96].

Epithelial–mesenchymal transition (EMT) is significantly associated with the progression of cancer, as it increases the malignancy of the tumor and enhances its ability to metastasize to distant sites [97]. A study on A549 cells (human alveolar epithelial cancer cells) exposed to PS-NPs induced a two-fold increase in cell migration, together with upregulation of matrix metallopeptidase 2 (MMP2) and decreased E-cadherin, both of which are key markers of EMT [61]. This was further accompanied by elevated ROS and NADPH oxidase 4 (NOX4; a ROS generator) levels, which are mediated by the NOX4 gene, and it was concluded that the smaller the size of the PS-NPs, the stronger the toxic effects. Similarly, Schreiber et al. reported greater uptake and migration potential of smaller PS-MPs (0.25 µm and 1 µm) in colorectal cancer cells (HT29, HCT116, SW480, and SW620), with particles internalized via energy-dependent endocytosis and retained across cell divisions [98]. The study demonstrated that particles smaller than 1 µm can enhance cell migration, potentially promoting metastasis. Xu and colleagues found various types of MPs (mainly PE and PP) in cervical cancer tissues (2.24 ± 1.61 MP particles/g) and indicated that MP levels increased with cancer progression, suggesting potential accumulation in tumor tissues [14]. Moreover, metabolomic examinations demonstrated substantial upregulation of amino sugar and nucleotide sugar metabolism pathways, which was proposed as a contributory mechanism for pathogenesis in cervical cancer. In breast cancer models (MDA-MB-231-DSP1-7), PS-NPs (0.5, 1.0, 4.5 µm; 4000–64,000 particles/mL for 24 h) were more readily internalized, promoting proliferation and slightly more migration than in normal breast epithelial cells (M13SV1_Syn1-DSP8-11) in a dose- and size-dependent manner [99]. Park and colleagues observed that PP-MPs (0.4–2 mg/mL for 24 h) did not significantly impact viability or migration in MDA-MB-231 and MCF-7 cells (human breast cancer models) [100]. However, RNA sequencing analysis in MDA-MB-231 cells revealed upregulation of cell cycle genes (notably TMBIM6, AP2M1, and PTP4A2) and IL-6 (a pro-inflammatory cytokine), suggesting pro-oncogenic inflammation and G1/S phase transition, which promotes proliferation and metastasis in cancer cells.

Exposure to MNPs has also been linked to the development of resistance to antineoplastic agents (Table 3). Kim et al. found that long-term PS-MP exposure (9.5–11.5 µm; 8.61 × 10⁵ particles/mL, 4 weeks) enhanced proliferation and invasion in gastric cancer cells (AGS, MKN1, MKN45, NCI-N87, KATOIII) [68]. Moreover, cytotoxicity data revealed that the cancer cells exposed to PS-MPs were resistant to commonly used anticancer drugs like bortezomib, cisplatin, paclitaxel, gefitinib, lapatinib, sorafenib, and trastuzumab, driven by CD44 and ASGR2 upregulation. Interestingly, while in vivo administration of PS-MPs in an NCI-N87 xenograft mouse model also accelerated tumor growth and multidrug resistance against the same anticancer drugs, which was attributed to increased CD44 expression, knockdown of ASGR2 reversed these effects, highlighting its role in MP-induced tumor progression [68]. Additional molecular targets implicated in MP-related carcinogenesis include AP-2 complex subunit mu-1 (AP2M1), ASGR2), Bax inhibitor-1 (BI-1), and Ferritin Heavy Chain (FTH1), with molecular docking studies suggesting potential therapeutic interventions (e.g., goserelin, paclitaxel, raloxifene, and exemestane for breast cancer; epirubicin for gastric cancer; vemurafenib and trametinib for skin cancer; and paclitaxel and sorafenib for liver and lung cancers) [101]. Similarly, in colorectal cancer cells (HCT116, SW480), MPs (25 µg/mL) enhanced proliferation, migration, and invasion and reduced oxaliplatin sensitivity. Mouse xenograft models confirmed these effects, along with gut microbiome alterations and mTOR-mediated autophagy activation [20].

Table 3. Micro(nano)plastics involved in different types of cancer and their carcinogenic impact.

Type of Cancer	MP/NPs Involved	Model Organism	Carcinogenic Effect	Reference
Skin cancer	PE (1 µm; 0–1 mg/mL)	Skin squamous-cell carcinoma cells: SCL-1, A431	Increased proliferation of skin cancer cells with increased mitochondrial ROS and NLRP3-mediated inflammation	[94]
Breast cancer	PP (16.4 µm; 1.6 mg/mL)	Human breast cancer cells: MCF-7, MDA-MB-231	Breast cancer cells relatively resistant to PP-MPs induced cytotoxicity and promoted inflammation and metastasis	[100]
	PS-NPs (0.5, 1.0, 4.5 µm; 4000–64,000 particles/mL)	MDA-MB-231-DSP1-7	Dose- and size-dependent absorption of PS-MPs and enhanced proliferation and migration of cancer cells	[99]
Ovarian cancer	PS-NPs (100 nm; 10 mg/mL)	Mouse xenograft (human epithelial ovarian cancer cells; HEY)	Increased tumor growth in mice via THBD gene-mediated tumor microenvironment pathway	[102]
Lung cancer	PS-NPs (20–50 nm; 0–160 µg/mL)	Human alveolar epithelial cancer cells: A549	Increased cancer cell migration and EMT with NOX4-mediated oxidative stress	[103]
Colorectal cancer	PS-MPs (0.25, 1 µm; 0.16–5 µg/mL)	Human colorectal cancer cells: HT29, HCT116, SW480	Transfer of MP particles during cell division and increased cell migration	[98]
	MPs (60–80 nm; 25 µg/mL)	Human colorectal cancer cells: HCT116, SW480 Mouse tumor model (xenograft)	MP exposure increased proliferation and migration of colorectal cancer cells and enhanced protective autophagy of tumor cells by modulating mTOR pathway, leading to oxaliplatin resistance	[20]
Cervical cancer	PE-, PP-MPs (<20 µm; 2.24 ± 1.61 particles/g)	Cervical cancer tissues from patients	Increased MP exposure level with cervical cancer progression and enhanced amino sugar and nucleotide sugar metabolism pathways	[14]
Gastric cancer	PS-MPs (9.5–11.5 µm; 8.61 × 105 particles/mL)	Human gastric cancer cells: AGS, MKN1, MKN45, NCI-N87, KATOIII) Xenograft mouse model	Increased tumor proliferation, growth, and invasion and multidrug resistance of tumor cells against tested chemotherapeutic agents, mediated by the ASGR2 gene	[68]
	PE-, PP-MPs (37–75 µm)	Human gastric adenocarcinoma cells (AGS)	Increased proliferation and survival upon long-term exposure in both 2D and 3D cancer cell models	[96]
Glioblastoma	PE-MPs (37–75 µm; 0.62–20 mg/mL)	Human glioblastoma cells (U87)	Enhanced cellular proliferation and migration with increased capacity to form colonies (spheroids) upon both short and chronic exposure	[95]

Abbreviations: PE—polyethylene; PP—polypropylene; PS—polystyrene.

Table 3. Micro(nano)plastics involved in different types of cancer and their carcinogenic impact.

Type of Cancer	MP/NPs Involved	Model Organism	Carcinogenic Effect	Reference
Skin cancer	PE (1 µm; 0–1 mg/mL)	Skin squamous-cell carcinoma cells: SCL-1, A431	Increased proliferation of skin cancer cells with increased mitochondrial ROS and NLRP3-mediated inflammation	[94]
Breast cancer	PP (16.4 µm; 1.6 mg/mL)	Human breast cancer cells: MCF-7, MDA-MB-231	Breast cancer cells relatively resistant to PP-MPs induced cytotoxicity and promoted inflammation and metastasis	[100]
	PS-NPs (0.5, 1.0, 4.5 µm; 4000–64,000 particles/mL)	MDA-MB-231-DSP1-7	Dose- and size-dependent absorption of PS-MPs and enhanced proliferation and migration of cancer cells	[99]
Ovarian cancer	PS-NPs (100 nm; 10 mg/mL)	Mouse xenograft (human epithelial ovarian cancer cells; HEY)	Increased tumor growth in mice via THBD gene-mediated tumor microenvironment pathway	[102]
Lung cancer	PS-NPs (20–50 nm; 0–160 µg/mL)	Human alveolar epithelial cancer cells: A549	Increased cancer cell migration and EMT with NOX4-mediated oxidative stress	[103]
Colorectal cancer	PS-MPs (0.25, 1 µm; 0.16–5 µg/mL)	Human colorectal cancer cells: HT29, HCT116, SW480	Transfer of MP particles during cell division and increased cell migration	[98]
	MPs (60–80 nm; 25 µg/mL)	Human colorectal cancer cells: HCT116, SW480 Mouse tumor model (xenograft)	MP exposure increased proliferation and migration of colorectal cancer cells and enhanced protective autophagy of tumor cells by modulating mTOR pathway, leading to oxaliplatin resistance	[20]
Cervical cancer	PE-, PP-MPs (<20 µm; 2.24 ± 1.61 particles/g)	Cervical cancer tissues from patients	Increased MP exposure level with cervical cancer progression and enhanced amino sugar and nucleotide sugar metabolism pathways	[14]
Gastric cancer	PS-MPs (9.5–11.5 µm; 8.61 × 105 particles/mL)	Human gastric cancer cells: AGS, MKN1, MKN45, NCI-N87, KATOIII) Xenograft mouse model	Increased tumor proliferation, growth, and invasion and multidrug resistance of tumor cells against tested chemotherapeutic agents, mediated by the ASGR2 gene	[68]
	PE-, PP-MPs (37–75 µm)	Human gastric adenocarcinoma cells (AGS)	Increased proliferation and survival upon long-term exposure in both 2D and 3D cancer cell models	[96]
Glioblastoma	PE-MPs (37–75 µm; 0.62–20 mg/mL)	Human glioblastoma cells (U87)	Enhanced cellular proliferation and migration with increased capacity to form colonies (spheroids) upon both short and chronic exposure	[95]

Abbreviations: PE—polyethylene; PP—polypropylene; PS—polystyrene.

5. Impact of Micro(Nano)plastics on the Tumor Microenvironment and Contrasting Antitumor Effects

The tumor microenvironment (TME), which plays a crucial role in tumorigenesis, progression, metastasis, and resistance to antitumor therapy [104], has recently gained considerable interest as it is also affected by MNPs. Current research has indicated that MNPs can promote tumor growth and metastasis by altering the TME [102,105]. In a xenograft model of human epithelial ovarian cancer cells (HEY), PS-NPs (10 mg/mL, 27 days) significantly increased tumor growth and mitotic activity, with transcriptomic data revealing immune pathway activation, particularly via THBD gene expression [102]. Yang et al. showed that oral exposure to PE-/PS-NPs (10 mg/kg for one week) in mice elevated pro-inflammatory macrophages (CD45⁺ CD80+ F4/80⁺) in Peyer’s patches, increased IL-1β-producing macrophages, and altered Treg/Th17 differentiation in the colonic microenvironment, disrupting immune homeostasis and favoring tumorigenesis [66].

In contrast to the above studies highlighting the tumor-promoting effects of MNPs, few studies have reported the tumor-inhibitory effects of MNPs [101,106,107,108,109]. For instance, polymethyl methacrylate particles (PMMA; 3–10 µm, 0.25–1 mg/mL for 72 h) reduced viability in a co-culture model of human hepatocellular carcinoma (HepG2/THP-1), increased oxidative stress and inflammation, and disrupted lipid metabolism [107]. Moreover, PMMA particles (470 ± 4 nm, 1–7.5 µg/mL for 48 h) exposed to human colorectal carcinoma cells (HCT-116) and PE-MPs (5–60 µm, 0.25–1 mg/mL for 48 h) exposed to human colorectal adenocarcinoma cells (Caco-2 and HT-29) inhibited growth and induced oxidative stress, respectively [106,109]. Likewise, polyurethane MPs also suppressed proliferation in Caco-2 cells [108], while PS-NPs showed dose- and size-dependent cytotoxic effects in MDA-MB-231 cells [110]. These opposing findings underscore the complexity of MP–cancer cell interactions and highlight the need for further mechanistic investigations.

6. Limitations and Future Recommendations

Our knowledge of the role of MNPs in carcinogenesis is in its early stages of development and presents several challenges that require interdisciplinary research for a comprehensive understanding. Based on our review, we have identified key knowledge gaps in the existing literature and have suggested future research recommendations, which are highlighted in the following points.

6.1. Mechanistic Uncertainties

While oxidative stress, DNA damage, immune dysregulation, and inflammation have been identified as potential mechanisms for cancer initiation and progression, the precise molecular mechanisms of the carcinogenic effects of MNPs remain poorly characterized. Moreover, the majority of the existing literature is limited to cell cultures and animal experiments, which may not accurately represent the complex nature of human tissues. Studies on other models like xenografts, 3D organoids, and human-induced pluripotent stem cells (iPSCs), which are more human-relevant, are urgently required to precisely reveal molecular mechanisms of carcinogenesis.

Notably, some studies have also reported the tumor-inhibitory properties of MNPs, underscoring the dual nature of their effects on cancer cells [101,106,107,108,109]. Furthermore, the interaction between MNPs and the TME—comprising cancer cells, stromal elements, and extracellular matrix—remains poorly understood, despite the TME’s critical role in tumor development, progression, and therapeutic resistance. Future research should therefore focus on determining the cellular and molecular pathways by which MNPs influence carcinogenesis, with particular emphasis on their impact within the TME. Integration of multiomics technologies can further facilitate the identification of key carcinogenic pathways and biomarkers to gain better insight into MNP-induced carcinogenesis.

6.2. Experimental and Methodological Challenges

Another key gap is the use of high doses of MNPs in experiments, which do not accurately mimic the environmentally relevant, chronic low-dose exposures. Notably, some studies have reported no significant carcinogenic potential of MNPs when used in real-world concentrations [57,92,111]. Moreover, MNPs can be accidentally introduced during experimental procedures from laboratory materials or the environment, which may lead to false positive results. Additionally, most studies so far have focused on the size of MNPs as a key factor in their toxicity without considering the effects of shape, surface charge, and chemical alterations. Hence, future research should consider the possibility of contamination by foreign plastic particles during experiments and adopt strategies for preventing them. Furthermore, they should also take into account how the shape, surface charge, and any chemical modifications (functionalization) of these particles may influence their potential to cause cancer and other toxic effects.

Many studies have been limited by short-term MNP exposure durations (ranging from days to weeks), so there is a need for longitudinal studies that explore the long-term effects of chronic, low-level exposure to MNPs. Most current research has focused on commercially synthesized spherical PS particles, which represent less than 1% of the MNPs found in nature. There is a critical need to expand research to include other types of MNPs, including fragments of PE, PP, PA, PVC, and PET, which are more prevalent in the environment. Besides this, the lack of standardized and validated analytical methods for MNP characterization makes it difficult to compare results across studies, emphasizing the need for the development of specific, harmonized procedures for MNP characterization in future research.

6.3. Chemical Complexity of Plastic Additives

The majority of current studies have largely focused on the carcinogenic effects of specific plastic additives, particularly EDCs such as bisphenols and phthalates. However, plastics used in our daily life contain a complex mixture of several additives, many of which remain understudied for their impact on cancer progression. Likewise, the existing literature typically evaluates additives in isolation, which does not reflect actual exposure conditions where “cocktail effects” and synergistic interactions may occur. This further complicates the assessment of cancer risk from MNPs, as the potential release of these additive chemicals from plastic materials must also be considered. Future studies must shift from single-compound analyses to systematically investigate the combined carcinogenic impact of MNPs and additive mixtures.

6.4. Epidemiological Gaps

Most studies so far have been performed under controlled laboratory conditions, with a lack of large-scale and long-term epidemiological data linking MP exposure to cancer risk, which limits translation to real-world human exposure scenarios. Considering the chronic and latent nature of cancer, future research must prioritize longitudinal, population-based studies that link MNP exposure to cancer risk, as these could provide robust evidence to inform the development of evidence-based regulatory policies aimed at minimizing oncogenic risks.

6.5. Lack of Specific Biomarkers for Exposure Assessment

Another major challenge in MNP research is the lack of validated biomarkers that assess MNP exposure and predict carcinogenic risk. Current detection methods are limited by low specificity and sensitivity, making it difficult to establish exposure–response relationships in humans. Development of reliable biomarkers and technological innovation for detecting MNP exposure would greatly improve risk assessment and facilitate monitoring in high-risk populations, such as those with occupational exposure.

6.6. Innovative Therapeutic Potential

Recently, biodegradable plastics such as polylactic acid (PLA) and polylactic acid-glycolic acid (PLGA) have been investigated as drug carriers owing to their unique size and surface properties. Their use for the targeted delivery of anticancer agents has shown promising preliminary results. Notably, the use of modified PLA-MNPs loaded with chemotherapeutic and immunomodulating agents has resulted in enhanced tumor suppression [112,113]. These findings are in direct contrast with emerging reports on the tumorigenic potential of MNPs, highlighting a major gap in our understanding of their toxicity. Therefore, future studies should focus on in-depth safety and biocompatibility analyses of such bioplastic materials before utilizing them as drug delivery systems for cancer treatment.

6.7. Integrated and Interdisciplinary Approach

Because of the complexity of MNP-induced human carcinogenesis, a multidisciplinary collaboration integrating molecular biology, cell biology, toxicology, environmental science, and public health is required for a comprehensive understanding of this issue. In addition, international cooperation will be essential to drive technological innovation, harmonize biomonitoring methodologies, and address the global challenge of plastic pollution.