Emerging evidence on micro- and nanoplastics carcinogenicity: mechanisms, models, and signaling networks

Abstract

Evidence of micro- and nanoplastics (MNPLs) presence in human tissues, cells, and biological fluids raises concerns about their potential role in hazardous diseases, including cancer. Higher concentrations of microplastics (MPLs) in cancerous tissues compared with adjacent healthy tissues, particularly in barrier organs such as the lungs, intestines, and reproductive system, suggest a potential association with tissue pathology and tumor-related processes. Extracted MNPLs from cancerous tissues exhibit diverse polymer compositions and morphologies, predominantly fibers and fragments larger than 1 μm, while smaller nanoplastics (NPLs) are likely underrepresented due to detection limitations. To investigate how MNPLs promote carcinogenesis depending on their physicochemical characteristics, various in vitro and in vivo studies have been analyzed. Most studies use pristine commercial spherical polystyrene (PS) MNPLs, which do not fully exhibit real-life MNPL characteristics but still provide valuable insights into their hazardous effects across a wide size range. Additional studies employing alternative polymers and environmentally relevant particle shapes further advance understanding of MNPL-associated health risks, as addressed in this review. Existing data indicates that smaller NPLs readily cross biological barriers and accumulate within cells due to their high surface area, whereas larger MPLs primarily interact at tissue surfaces, causing physical stress, tight junction disruption, and microbiota perturbation. Notably, MNPL exposure induces multiple hazardous effects and disrupts cellular homeostasis through coordinated and integrated signaling pathways. NF-κB signaling triggers pro-inflammatory and survival gene expression, while JNK-MAPK, ERK1/2-MAPK, and JAK–STAT pathways amplify inflammation, DNA damage responses, and apoptosis. MNPLs also induce ROS-driven ER stress, mitochondrial dysfunction, and dysregulation of AKT, TP53, caspases, and XIAP, activating apoptosis, necroptosis, and fibrosis. Compensatory antioxidant responses are activated via NRF2/HO-1 to counteract oxidative stress, while β-catenin/Wnt signaling is concurrently modulated, linking ROS-induced stress to tumorigenic reprogramming and cellular proliferation. Dysregulation of metabolic and growth regulators, including PI3K–AKT–mTOR, AMPK, mTORC1, and P70S6K, promotes cellular proliferation, survival, and metabolic adaptation. Simultaneously, modulation of ECM–receptor interactions, focal adhesion, Hippo, TGF-β, and cell-cycle regulators (CDK4/6, Cyclin D1, p-Rb) reshapes the tumor microenvironment, supporting potential malignant progression. All these interconnected events establish a tumor-permissive environment, promoting uncontrolled proliferation, metabolic reprogramming, and malignant transformation, thereby supporting the potential role of MNPLs in carcinogenesis.