A research investigation published in Cancer and Metabolism reveals a direct mechanistic pathway connecting chronic environmental exposure to fine particulate matter and tobacco carcinogens with the accelerated progression of colorectal cancer through metabolic disturbance. Prolonged exposure to airborne fine particulate matter, commonly designated as PM 2.5, alongside 4-methylnitrosamino-1-3-pyridyl-butanone, a potent tobacco-specific nitrosamine known as NNK, has long exhibited epidemiological correlations with digestive tract malignancies. However, the precise cellular communication cascades and systemic metabolic alterations driving this malignant advancement have remained largely unresolved. Led by Shenghua Zhang, Dongfang Meng, and Jijin Wang, the research team demonstrated that these dual environmental toxic agents provoke hallmark characteristics of metabolic syndrome, prominently featuring elevated circulating fasting glucose and hyperlipidemia. Crucially, the researchers established that this carcinogen-induced systemic disruption alters the physiological behavior of stromal cells residing within the colorectal tumor microenvironment. By reshaping the metabolic phenotype and secretory profile of tumor-associated macrophages, the toxic combination coordinates immune evasion and sustains colorectal carcinoma advancement in experimental animal models.
To model systemic metabolic dysfunction, the investigators conducted longitudinal animal studies employing eight-week-old FVB mice exposed over twenty-eight weeks and C57BL/6 mice exposed for twenty weeks to combined regimens of NNK and PM 2.5. Serial biochemical assessments demonstrated pronounced shifts in circulating lipid and carbohydrate profiles, characterized by significant elevations in fasting and basal blood glucose concentrations accompanied by reduced high-density lipoprotein cholesterol and altered triglyceride levels. In physiological challenges, mice subjected to prolonged carcinogen exposure developed impaired glucose clearance during glucose tolerance tests and marked insulin resistance during insulin tolerance testing, despite maintaining circulating blood insulin concentrations that did not significantly differ from unexposed control groups. Furthermore, the exposed rodents exhibited measurable reductions in overall body weight and systolic blood pressure relative to controls. When luciferase-labeled human colorectal cancer cells, designated HCT116-Luc, were subcutaneously xenografted into C57BL/6 mice following twenty weeks of prior carcinogen conditioning, subsequent tumor development was substantially accelerated compared to unexposed animals.
Recognizing that metabolic syndrome encompasses intricate nutritional interactions, the researchers evaluated whether dietary macronutrients influenced carcinogen-mediated tumorigenesis in orthotopic colon cancer models established via intracecal injection of HCT116-Luc cells. Cohorts of eight-week-old C57BL/6 mice received either normal chow, a high-carbohydrate diet, or a high-fat diet, administered alone or with continued NNK and PM 2.5 exposure for eight additional weeks. Animals sustained on the high-carbohydrate diet alongside carcinogen challenge exhibited dramatic surges in primary colonic tumor burden and extensive metastatic dissemination across distant organ sites, including liver, lungs, brain, spleen, and thoracic cages. Interestingly, high-fat dietary feeding failed to induce equivalent pro-metastatic enhancement. To verify whether excessive glycolytic flux sustained this progression, the investigators administered the competitive hexokinase inhibitor 2-deoxy-D-glucose, known as 2DG, to high-carbohydrate and carcinogen-exposed animals. Pharmacological glycolytic blockade with 2DG markedly suppressed primary tumor expansion, abolished distant metastases, restored reactive oxygen species levels in colon, liver, and brain tissues, and significantly prolonged overall animal survival.
To uncover whether environmental carcinogens acted directly upon neoplastic cells or operated through stromal intermediates, the researchers performed assays on cultured human colorectal cancer cell lines, including HCT116 and SW480. Eight continuous weeks of direct exposure to NNK and PM 2.5 produced no enhancement in cancer cell colony formation, spherical growth, or transwell migration, indicating that carcinogens did not drive tumor aggression through intrinsic cellular alterations alone. Instead, immunofluorescent characterization of orthotopic colon tissues revealed extensive infiltration of CD45-positive leukocytes and F4/80-positive tumor-associated macrophages in carcinogen-exposed, carbohydrate-fed mice. Fluorescence-activated cell sorting and transcriptional profiling demonstrated that these infiltrating macrophages expressed elevated levels of hallmark M2-like markers, such as Arg1 and CD206, without upregulating inducible nitric oxide synthase. Depletion of macrophages in vivo using clodronate-encapsulated liposomes profoundly suppressed orthotopic tumor growth, prevented metastatic dissemination across visceral organs, and substantially prolonged the survival of carcinogen-challenged mice, demonstrating that tumor-associated macrophages are obligatory stromal executors of pollutant-driven disease progression.
Investigating the mechanisms behind heightened macrophage activity, hybrid positron emission tomography and magnetic resonance imaging utilizing 18F-fluorodeoxyglucose demonstrated significantly elevated standardized uptake value ratios in colon tumors from carcinogen-exposed animals. Real-time polymerase chain reaction and immunofluorescent staining revealed marked upregulation of two pivotal glucose transporters, GLUT1, encoded by Slc2a1, and GLUT3, encoded by Slc2a3, selectively localized to F4/80-positive macrophages within colonic stroma. In vitro dissection of THP-1 human monocytes established that transporter induction occurred via a coordinated two-step signaling mechanism. Airborne PM 2.5 acted through intracellular aryl hydrocarbon receptors to transcriptionally activate SLC2A1 and SLC2A3 gene expression in a dose- and time-dependent manner, whereas tobacco-derived NNK acted through nicotinic acetylcholine and beta-adrenergic receptors to stimulate the translocation of GLUT1 and GLUT3 proteins to the plasma membrane. Pharmacological disruption using the aryl hydrocarbon receptor antagonist SR1, nicotinic blocker mecamylamine, or beta-adrenergic inhibitor propranolol completely abolished carcinogen-induced transporter upregulation and prevented macrophage uptake of the fluorescent glucose analogue 2-NBDG.
Metabolic flux analyses using extracellular flux analyzer technology confirmed that macrophages isolated from carcinogen-exposed colonic tissues and THP-1 monocytes treated with NNK and PM 2.5 exhibited significantly higher extracellular acidification rates and elevated oxygen consumption rates, coupled with increased adenosine triphosphate production. This heightened glycolytic state enabled macrophages to substantially increase their transcription and secretion of insulin-like growth factor 2, designated IGF2, an induction that intensified progressively when cells were cultured in media containing elevated glucose concentrations reaching ten grams per liter. Culturing naive HCT116 colorectal cancer cells in conditioned media harvested from carcinogen-primed, high-glucose macrophages dramatically elevated cancer cell colony proliferation and sphere formation. Conversely, blocking macrophage glycolysis with 2DG, genetically deleting IGF2 in macrophages using CRISPR/Cas9 targeting, or neutralizing extracellular IGF2 using specific antibodies completely abrogated this tumor-promoting activity. In co-injection xenograft animal experiments, mice co-inoculated with colorectal cancer cells and control macrophages pretreated with carcinogens developed aggressive, rapidly growing tumors, whereas tumors failed to expand when co-injected with macrophages carrying targeted genetic deletions of IGF2.
Exploring how macrophage-derived IGF2 altered colorectal cancer cell signaling, receptor tyrosine kinase phosphorylation profiling revealed that conditioned media from carcinogen-exposed macrophages hyper-activated insulin receptors in cancer cells to a substantially greater extent than insulin-like growth factor 1 receptors. Biochemical fractionation and streptavidin pull-down experiments on biotinylated surface proteins revealed an unexpected non-canonical signaling trajectory: upon sustained IGF2 stimulation, phosphorylated insulin receptors detached from the cancer cell membrane, entered the cytosol, and rapidly translocated into the nucleus within thirty minutes. Chromatin fractionation confirmed that phosphorylated insulin receptors became directly integrated into nuclear chromatin fractions. The investigators demonstrated that this nuclear translocation process was actively facilitated by importin machinery, specifically relying upon importin subunit alpha-2, known as KPNA2, and importin subunit beta-1, known as KPNB1. Co-immunoprecipitation confirmed that IGF2 treatment promoted the assembly of an import complex comprising the insulin receptor alongside KPNA2 and KPNB1. Silencing either KPNA2 or KPNB1 using small interfering RNA constructs completely abolished the nuclear accumulation of phosphorylated insulin receptors, trapping the receptor in the cytoplasm and attenuating downstream oncogenic activation.
To identify nuclear binding partners and downstream targets of imported insulin receptors, the research team integrated immunoprecipitation mass spectrometry with proteomic profiling across multiple colorectal cancer lines, including HCT116, SW480, HT-29, Caco-2, and SNU-C2A. These analyses identified nucleophosmin 1, designated NPM1, as a prominent interacting co-activator that physically binds to the nuclear insulin receptor. Detailed domain mapping using full-length and truncation mutants established that insulin receptors interact specifically with the histone-binding domain of NPM1, creating a transcriptional complex that incorporates RNA polymerase II and core histones. Chromatin immunoprecipitation assays demonstrated that this nuclear complex binds directly to the P3 promoter region, spanning nucleotides 469 to 690, of the CD274 gene encoding programmed cell death ligand-1, or PD-L1. Luciferase reporter assays confirmed that this interaction stimulated CD274 transcription, driving overexpression of PD-L1 alongside essential antioxidant defense genes, including HO-1, NQO1, GCLC, and GCLM. Ablating NPM1 or insulin receptors using short hairpin RNA prevented PD-L1 induction, depleted antioxidant enzymes, caused reactive oxygen species accumulation, and markedly impaired both sphere formation and lung metastasis.
The therapeutic importance of this signaling axis was confirmed in orthotopic colon cancer models subjected to high-carbohydrate feeding and environmental carcinogen exposure. Systemic administration of a PD-L1-neutralizing monoclonal antibody suppressed bioluminescent tumor growth, significantly reduced metastatic tumor multiplicity and overall tumor burden within liver and lung tissues, and extended overall survival rates compared to untreated mice. Moving beyond animal models, the investigators validated clinical relevance using patient-derived biological specimens. Quantifying plasma concentrations of total 4-methylnitrosamino-1-3-pyridyl-1-butanol, known as NNAL, the principal stable circulating metabolite of NNK, revealed strong positive correlations with fasting blood glucose, serum triglycerides, C-reactive protein, advanced tumor-node-metastasis stages, and regional lymph node metastasis, alongside negative correlations with high-density lipoprotein cholesterol. In a tissue microarray containing thirty-two annotated colorectal cancer specimens, patients with positive N1 or N2 lymph node metastases exhibited significantly higher expression of GLUT1 and IGF2 in CD68-positive tumor-associated macrophages, paired with elevated phosphorylated insulin receptor and PD-L1 levels in neoplastic tissues. Survival analysis of TCGA datasets confirmed that high expression of GLUT1 or GLUT3 strongly correlates with decreased overall and disease-free survival.
Despite providing a comprehensive mechanism connecting environmental pollutants and dietary carbohydrates to immunosuppressive colorectal cancer progression, the authors outlined several important experimental limitations. First, all in vivo mechanistic discoveries relied upon murine xenograft and orthotopic models characterized by fixed genetic lineages and relatively short exposure periods, which cannot fully replicate decades-long, low-dose environmental inhalation patterns and complex clinical comorbidities, such as obesity and type 2 diabetes, encountered in human populations. Second, the research focused almost exclusively on tumor-associated macrophages, leaving unexamined potential contributions of other stromal populations, such as cancer-associated fibroblasts and endothelial cells, which also participate in microenvironmental metabolic cross-talk. Third, clinical validations were conducted using a modest tissue microarray cohort comprising thirty-two patients, necessitating broader multicenter confirmation in larger cohorts. Fourth, while pharmacological inhibitors targeting glycolysis, macrophage viability, and PD-L1 demonstrated efficacy in mice, their pharmacokinetics, safety profiles, and combinatorial potential with standard chemotherapies remain to be clarified. Finally, because receptor pathway characterization partly depended on small-molecule inhibitors carrying theoretical off-target risks, future studies utilizing refined genetic knockouts will be essential to corroborate the NNK-AChR and PM 2.5-AhR regulatory axes.
Subject of Research: Mechanisms linking particulate matter, tobacco carcinogen exposure, and metabolic reprogramming to colorectal cancer progression
Article Title: Fine particulate matter and tobacco product exposure exacerbates metabolic syndrome-related colon cancer via regulating oxidative stress and tumor-associated macrophage interactions
Article References: Zhang, S., Meng, D., Zhang, H., Pan, F., Gao, Y., & Wang, J. (2026). Fine particulate matter and tobacco product exposure exacerbates metabolic syndrome-related colon cancer via regulating oxidative stress and tumor-associated macrophage interactions. Cancer & Metabolism, 14(1), Article 27. https://doi.org/10.1186/s40170-026-00442-5
Image Credits: AI Generated
DOI: 10.1186/s40170-026-00442-5
Keywords: Colorectal Cancer, Particulate Matter, Tobacco Carcinogens, Metabolic Syndrome, Tumor-Associated Macrophages, Insulin Receptor, PD-L1, Glycolysis, Fine, particulate, matter, tobacco
News Source: Nathaniel Bowman. (November 6, 2026). Air Pollutants and Tobacco Carcinogens Drive Colon Cancer via Metabolic Reprogramming. Scienmag.
