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A93-04 Microplastics Induce Bioenergetic Dysfunction and Impair Macrophage-mediated Anti-tumor Immunity
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Tiny plastic particles that we breathe in every day may weaken the immune cells in our lungs that normally hunt down and destroy cancer cells, according to a new mouse and lab-based study. Researchers found that these microplastics get stuck inside lung immune cells (macrophages), disrupt their energy production, and trigger changes that make them worse at fighting tumors—and mice exposed to microplastics developed larger tumors afterward. While this research is still early and hasn't been proven in humans, it offers a possible clue as to why lung cancer is rising in people who have never smoked.
Abstract Rationale Since the 1950s, micro- and nanoplastics (MNPs) have become omnipresent, representing a novel environmental hazard which continually deposits in our airways. Concurrently, there has been a rapid increase in lung cancer in never-smokers which cannot be attributed to genetic alterations. Although MNPs have been identified in the lung, if and how they promote lung disease and/or cancer remains unknown. Methods Mice were administered intranasal MNPs and lung function and pathology determined. Pulmonary macrophages (pMacs) were isolated for RNA-sequencing. Additional cohorts were inoculated with Lewis lung carcinoma (LLC) cells post-MNPs and tumor burden measured. Human monocyte-derived macrophages and macrophage cell lines were co-cultured in vitro with 0.02-10μm polystyrene, polyamine, and polyethylene MNPs and assessed for antigen processing, T cell stimulation, tumor phagocytosis, and bioenergetics. MNP-treated human precision-cut lung slices (PCLS) were assessed for markers of EMT and fibrosis. Results After 7-days, murine pMacs retained MNPs and upregulated pro-inflammatory IRF8/JUN/NF-kb with loss of muscarinic acetylcholine signaling, indicative of unchecked inflammation associated with fibrosis and EMT. When co-cultured in vitro, MNPs induced FOXM1 and IL-13/STAT6/ZEB1 signaling programs in macrophages associated with tissue repair and cancer metastasis. By contrast, diesel exhaust particulate (DEP) induced AHR signaling due to oxidative stress. Mechanistically, intracellular MNPs displace mitochondrial in macrophages, reducing mitochondrial mass, polarization, and oxidative phosphorylation which may be partially restored with the AMPK agonist AICAR. Interestingly, compared to DEP, MNP-treated macrophages increase expression of the mitochondrial genes ND6 and ATP8, subunits of the electron transport chain, potentially compensating for bioenergetic disruption. Pretreatment with MNPs reduced the ability of macrophages to phagocytose tumor cells in a dose and size dependent manner. MNPs impaired protein antigen processing in macrophages and T cell stimulation due to reduced antigen uptake into MNP loaded phagolysosomes. Additionally, MNPs induced expression of PD-1/PD-L1 on macrophages, which inhibited T cell stimulation and could be restored by antibodies blocking PD-1/PD/L1. MNPs embed within PCLS resulting in the loss of E-cadherin and gain of N-cadherin/α-SMA after 7-days. Finally, preliminary findings suggest that MNPs induce restrictive changes in the lung with decreased FEV0.05, and FEV0.1/FVC, and increase tumor burden in mice following LLC challenge. Conclusions These findings indicate that MNPs impair macrophages via unique mechanisms which include bioenergetic dysfunction. Loss of anti-tumor capabilities in MNP-laden macrophages may compromise cancer surveillance and elimination. As such, MNPs may have the potential to increase susceptibility to lung disease independent of the conventional mechanisms of inflammation and oxidative stress. This abstract is funded by: Department of Defense, Department of Cardiothoracic Surgery University of Pittsburgh School of Medicine
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The Indigestible Burden of Microplastics Drives Bioenergetic Dysfunction in Macrophages
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Scientists found that immune cells called macrophages—your body's cleanup crew—can swallow microplastics but can't actually break them down or get rid of them. Instead, the trapped plastic wraps up the cells' internal "power plants," draining their energy and making them worse at fighting infections and clearing out old or damaged cells. Over time, this may lead to ongoing, low-grade inflammation in the lungs that could contribute to chronic lung disease and even lung cancer.
Microplastics inhibit macrophage bioenergetics impairing homeostatic function and immune responsiveness
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Scientists found that when tiny plastic particles from our environment get breathed into the lungs, they weaken the "cleanup crew" immune cells (called macrophages) that normally fight off germs and cancerous cells by sapping their energy production. This damage made it harder for these cells to detect threats and alert the rest of the immune system—suggesting that inhaled microplastics could quietly raise our risk of infections and disease over time, even without causing obvious inflammation. The good news: in lab tests, the researchers found the cell damage could potentially be reversed with existing drugs, pointing to possible future treatments.
Inhaled Microplastics Inhibit Tissue Maintenance Functions of Pulmonary Macrophages
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Researchers found that inhaled microplastics accumulate in lung macrophages, the immune cells responsible for cleaning and maintaining lung tissue, and significantly impair their normal functions. The microplastic-laden macrophages showed reduced ability to perform tissue maintenance tasks that are essential for lung health. The study provides evidence that breathing in microplastics could compromise the lung's built-in defense and repair systems, with potential implications for respiratory health.
Microplastic-Induced Macrophage Dysfunction Drives Lung Tumor Progression through Glutathione Imbalance
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Researchers found that microplastics trigger a cascade of immune dysfunction in macrophages through toll-like receptor signaling, leading to disrupted glutathione metabolism and macrophage cell death via ferroptosis. In tumor-bearing mice, orally ingested microplastics accumulated in the lungs and remodeled the immune microenvironment over time, with increased infiltration of inflammatory macrophages and impaired lymphocyte function accompanying greater tumor burden.
Effects of microplastics on the colorectal tumor immune microenvironment and immunotherapy resistance via JAK–STAT–microbiota perturbation.
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Scientists found that microplastics—tiny plastic particles now common in our environment—can build up in colorectal (colon) tumors and make cancer immunotherapy less effective, based on studies in mice. The plastics seem to weaken the immune system's ability to find and attack cancer cells, partly by disrupting gut bacteria and blocking key immune signals. While this research was done in animals rather than people, it raises concerning questions about whether everyday plastic exposure could affect cancer treatment outcomes in humans.
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