Multifaceted mechanisms by which environmental endocrine-disrupting chemicals promote cancer progression: crosstalk among carcinogenesis, immunity, and metabolic reprogramming: narrative mini-review.

Clinical failure in oncology is frequently associated with the emergence of therapy-resistant phenotypes under selective treatment pressure ( Chen et al., 2025 ). Although therapeutic resistance has traditionally been attributed to intrinsic genomic instability, clonal evolution, drug efflux, and adaptive survival signaling, emerging evidence suggests that exogenous environmental exposures may also influence cellular states relevant to treatment response ( Lagunas-Rangel, 2026 ). In the context of EDCs, these effects should be interpreted cautiously, as direct clinical evidence remains limited and varies by compound class, cancer type, exposure window, and therapeutic context. Nevertheless, selected EDCs have been reported to modulate stress adaptation, programmed cell death, epithelial–mesenchymal transition (EMT), mitochondrial function, receptor-mediated survival signaling, and metabolic plasticity, thereby potentially creating biological conditions that favor therapy-related adaptation ( Lagunas-Rangel, 2026 ; Cortes-Ramirez et al., 2024 ). PFAS provide one of the clearest experimental examples linking EDC exposure to chemoresistance-related phenotypes. Although PFAS exposure has been associated with adverse outcomes in gynecologic cancer-related settings, the causal mechanisms linking PFAS to clinical chemoresistance remain incompletely defined ( Cortes-Ramirez et al., 2024 ). Recent investigations by Rickard et al. demonstrated that combined PFAS exposure enhanced cell survival in human ovarian cancer models following carboplatin treatment ( Rickard et al., 2022 ). This phenotype was accompanied by marked mitochondrial dysfunction, suggesting that PFAS may contribute to platinum-tolerant cellular states by altering mitochondria-mediated energy metabolism and increasing the apoptotic threshold ( Rickard et al., 2022 ). In addition, selected PFAS have been linked in experimental models to EMT, chemoresistance-associated cellular phenotypes, autophagic dysregulation, m6A modification, and PI3K–Akt/HIF-1 signaling ( Yu et al., 2025 ; Rickard et al., 2025 ; Qian et al., 2025 ). These findings suggest that PFAS may influence therapy-related adaptation through the convergence of mitochondrial stress, altered programmed cell death, metabolic remodeling, and EMT-associated plasticity, although validation in longitudinal clinical cohorts remains necessary. Bisphenol compounds may also contribute to therapy-related adaptive phenotypes through receptor-mediated signaling, tumor-suppressor disruption, and metabolic remodeling. BPA can engage a multi-receptor network, including ERα, ERβ, GPER, membrane-associated ERs, thyroid hormone receptors, and AR ( Vandenberg et al., 2009 ). In cancer-related models, BPA and its analogs have been reported to activate downstream pathways such as ERK1/2, PI3K–Akt, PKD1, and GPER–FAK–Src–ERK signaling, which are associated with proliferation, migration, anchorage-independent growth, and invasive phenotypes ( Merzoug-Larabi et al., 2019 ; Castillo-Sanchez et al., 2020 ; Donini et al., 2020 ; Zhao Q. et al., 2019 ). Importantly, BPA exposure has been associated with p53 inactivation in human cancer cells, potentially weakening DNA damage responses and apoptosis-related tumor-suppressive mechanisms ( Jiang et al., 2025 ; Chuang et al., 2020 ; Zhou et al., 2018 ). In BC models, dibutyl phthalate (DBP) and butyl benzyl phthalate (BBP) have been shown to accelerate MDA-MB-231 xenograft tumor growth, suggesting that phthalates can support aggressive tumor behavior under experimental conditions ( Hsieh et al., 2012 ). Although these observations do not directly establish phthalate-induced treatment resistance, they suggest that phthalate-associated metabolic and proliferative changes may be relevant to tumor-cell stress adaptation. Compared with phthalates, PCBs provide a more direct mechanistic link between metabolic rewiring, EMT, and aggressive tumor phenotypes. The quinone-type PCB metabolite PCB29-pQ has been reported to induce GLUT1 expression and activate the GLUT1/integrin β1/Src/FAK signaling cascade, thereby promoting EMT, extravasation, and metastatic dissemination ( Qin et al., 2022 ; Zhao H. et al., 2019 ). Since EMT and altered glucose uptake are frequently associated with adaptive survival states in cancer, PCB29-pQ-associated glycolytic reprogramming and EMT-like transition may represent a plausible route through which persistent pollutants contribute to therapy-related phenotypes. Beyond local tumor effects, PCBs have also been associated with systemic metabolic disorders, including obesity and type 2 diabetes, as well as altered fatty acid biosynthesis and activation pathways, particularly under mixed-exposure conditions involving other EDCs such as DDT and PFAS(97, 103). These systemic metabolic disturbances may further shape a tumor-supportive environment that affects nutrient availability, inflammatory signaling, and stress tolerance. AhR-related signaling and oxidative stress may serve as additional mechanistic bridges linking EDC exposure to therapy-related adaptation. Heavy metals and dioxin-like compounds can induce oxidative stress and activate ROS-associated signaling networks ( Elbekai and El-Kadi, 2004 ; Pekmezci et al., 2025 ; Anwar-Mohamed et al., 2009 ). In particular, Cr(VI)-induced oxidative stress may trigger oxylipin production and subsequent AhR activation, while Cd exposure has also been reported to upregulate AhR-related pathways and modulate pro-tumorigenic gene expression ( Anwar-Mohamed et al., 2009 ). These ROS–AhR-related effects may interact with inflammatory signaling, metabolic remodeling, and apoptosis-related pathways, thereby contributing to cellular states that are more tolerant of stress. However, direct evidence linking EDC-induced AhR activation to clinically established therapeutic resistance remains limited and should be regarded as mechanistically plausible rather than definitive. Overall, EDC-associated therapeutic resistance is best understood as a multi-layered adaptive framework rather than a single linear pathway. Based on the available evidence, selected EDCs may influence therapy-related phenotypes through several interconnected mechanisms: disruption of DNA damage responses and p53-mediated apoptosis; mitochondrial dysfunction and increased apoptotic threshold; activation of receptor-mediated survival pathways such as ERK, PI3K–Akt, PKD1, and FAK/Src signaling; EMT-associated plasticity and invasive transition; and metabolic adaptation involving glycolysis, lipid metabolism, nucleotide biosynthesis, oxidative phosphorylation, and redox homeostasis ( Merzoug-Larabi et al., 2019 ; Castillo-Sanchez et al., 2020 ; Donini et al., 2020 ; Zhao Q. et al., 2019 ; Yu et al., 2025 ; Rickard et al., 2025 ; Qian et al., 2025 ; Qin et al., 2022 ; Rickard et al., 2022 ; Zhao H. et al., 2019 ; Zhao et al., 2022 ; Liu et al., 2020 ; Ma et al., 2021 ; Huang et al., 2020 ; Zhao C. et al., 2019 ; Dairkee et al., 2012 ). These mechanisms provide a plausible basis for linking endocrine disruption, metabolic rewiring, and therapy-related adaptation. Future studies should integrate exposure assessment, treatment-response data, patient-derived models, and multi-omic profiling to determine whether EDC-associated molecular signatures can predict therapeutic response, recurrence risk, or resistance-associated tumor phenotypes in clinically relevant settings.

Global cancer burden is accelerating; by 2050, annual incidences are expected to reach 35.3 million, a 76.6% increase from the 2022 estimate of 20.0 million cases ( Bizuayehu et al., 2024 ), although the underlying etiologies remain multifaceted ( Hanahan, 2026 ). Beyond conventional risk factors, such as tobacco use, excessive alcohol consumption, oncogenic infections, and ionizing radiation, metabolic stressors like obesity and diabetes are increasingly recognized ( Swanton et al., 2024 ). Nevertheless, these established factors account for only a fraction of total cancer incidence, underscoring the need to better characterize overlooked environmental contributors to cancer risk. Exposure to endocrine-disrupting chemicals (EDCs) is estimated to account for 56.52% of all-cause mortality, corresponding to approximately 1.53 million deaths and an economic toll of roughly USD 189.7 billion ( Fan et al., 2023 ). Representative EDCs include bisphenol compounds, particularly bisphenol A (BPA), organochlorine compounds such as dichlorodiphenyltrichloroethane (DDT) and polychlorinated biphenyls (PCBs), polybrominated flame retardants, alkylphenols, and phthalates ( Ahn and Jeung, 2023 ). Crucially, even sub-threshold or low-level exposure to phthalates, polycyclic aromatic hydrocarbons, phytoestrogens, and toxic metals has been linked to substantial healthcare expenditures and societal health burdens. With a substantial proportion of identified EDCs exhibiting tumor-relevant biological activity ( Pan et al., 2023 ; Dou et al., 2026 ), these chemicals have been implicated in the pathogenesis and progression of hormone-sensitive malignancies, such as ovarian cancer, breast cancer (BC), and prostate cancer (PCa) ( Liu et al., 2023 ; Macedo et al., 2023 ). However, this figure is likely an underestimate due to the absence of mandatory testing and the long clinical latency of EDC-associated oncogenesis ( Modica et al., 2023 ). Beyond initial carcinogenesis, EDCs may influence tumor evolution by perturbing hormonal signaling, metabolic flux, and the tumor microenvironment (TME), including immune components, thereby contributing to metabolic reprogramming and therapy-related adaptive responses ( Lee et al., 2024 ; Czaczkowska et al., 2025 ). Given the escalating socioeconomic burden and complex multi-organ interactions of EDCs ( Modica et al., 2023 ; Feijó et al., 2025 ), this review aims to move beyond a chemical-by-chemical summary and instead develop an integrated mechanistic framework for understanding EDC-associated cancer-related processes. Unlike previous reviews that have primarily focused on individual EDC classes, hormone-dependent carcinogenesis, or isolated tumor microenvironmental effects, this review emphasizes a unified model linking endocrine signaling disruption, tumor immune microenvironment (TIME) remodeling, metabolic rewiring, epithelial–mesenchymal transition (EMT), tumor progression, and therapy-related adaptation. Specifically, we synthesize evidence across representative EDC classes, including bisphenols, PFAS, heavy metals, pesticides, phthalates, and PCBs, and identify shared regulatory hubs such as ER/AR/GPER, AhR, PPARs, PI3K–AKT–mTOR, AMPK, NF-κB, ROS, mitochondrial dysfunction, glycolysis, lipid metabolism, and immune suppression. By integrating receptor-level disruption, immune remodeling, and metabolic reprogramming into a single crosstalk-based framework, this review provides a translational perspective for understanding how chronic environmental exposure may influence cancer susceptibility, progression, and therapeutic response.

The health hazards associated with EDCs are characterized by significant latency periods and insidious physiological effects ( De Paula Nunes et al., 2026 ). Physiological shifts triggered during critical early-life developmental windows can permanently alter susceptibility to non-communicable diseases (NCDs), which have reached unprecedented prevalence globally ( Organization, 2014 ). The four primary NCD categories, cancer, cardiovascular diseases, chronic respiratory diseases, and diabetes, account for approximately 36 million annual deaths, disproportionately affecting low- and middle-income countries ( Gore et al., 2015 ). There is increasing scientific consensus that chronic, lifelong exposure to low-dose EDCs contributes substantially to this global burden by “programming” disease risk that manifests only in adulthood. We further organized the evidence into a convergent mechanistic framework. This framework emphasizes that structurally diverse EDCs may affect cancer-related phenotypes through shared receptor, metabolic, inflammatory, and immune-regulatory hubs rather than through completely independent pathways. A central contribution of this review is the integration of diverse EDC-related findings into a shared mechanistic framework. Rather than treating bisphenols, PFAS, heavy metals, pesticides, phthalates, and PCBs as independent toxicological categories, we highlight their convergence on common receptor, inflammatory, immune-regulatory, and metabolic hubs. This scope distinguishes the present review from previous EDC–cancer reviews by emphasizing the crosstalk among endocrine signaling disruption, TIME remodeling, metabolic rewiring, EMT, tumor proliferation, and therapy-related adaptation. Such an integrated perspective is particularly important because real-world exposure is chronic, low-dose, and mixture-based, making single-compound or single-pathway models insufficient to capture the biological complexity of EDC-associated cancer-related processes. In real-world scenarios, exposure rarely involves isolated agents; instead, humans encounter complex chemical “cocktails.” Long-term exposure to mixtures of persistent organic pollutants (POPs) can elicit cumulative, additive, or synergistic actions that significantly amplify pathological risks ( Lauretta et al., 2019 ). The rising incidence of hormone-related malignancies has intensified scrutiny of EDCs. Some toxicological screening profiles suggest that up to 80% of identified EDCs may display tumor-relevant biological activities; however, this does not necessarily indicate definitive carcinogenicity in humans ( Sung et al., 2021 ; Pierozan et al., 2020 ; Rocha et al., 2021 ). Despite rigorous oversight by agencies such as the U.S. U.S. Environmental Protection Agency (EPA) and the Food and Drug Administration (FDA), the environmental persistence of legacy contaminants ensures they remain a developmental threat decades after their official phase-out ( Houston and Ghosh, 2020 ). This necessitates regulatory frameworks that address not only contemporary chemical usage but also the risks posed by environmental persistence. Three exposure-related dimensions should be emphasized when interpreting EDC-associated cancer-related effects: mixture exposure, low-dose non-monotonic responses, and critical developmental windows. First, real-world EDC exposure rarely involves isolated compounds. Instead, humans are exposed to complex chemical mixtures, particularly persistent organic pollutants, which may exert cumulative, additive, or synergistic biological actions ( Lauretta et al., 2019 ). This mixture-based exposure pattern may partly explain why single-compound studies cannot fully capture the biological complexity of environmental contaminants. Second, the conventional toxicological paradigm based on high-dose linear responses is increasingly challenged by evidence that some EDCs can perturb endocrine and metabolic homeostasis at picomolar or nanomolar concentrations and may produce non-monotonic dose–response patterns ( Xu et al., 2025 ). Therefore, effects observed at low doses cannot always be predicted from high-dose models. Third, exposure timing is a critical determinant of long-term biological consequences. Evidence from bisphenol, PFAS, pesticide, and PCB-related studies suggests that prenatal, neonatal, pregnancy-related, and lactational exposure windows may influence tissue architecture, endocrine responsiveness, metabolic programming, and later cancer susceptibility ( Wormsbaecher et al., 2020 ; Wang et al., 2016 ; Cohn et al., 2020 ; Mancini et al., 2020 ; Bonefeld-Jørgensen et al., 2014 ; Bräuner et al., 2021 ; Swartz et al., 2022 ; Danjou et al., 2021 ; Paul et al., 2023 ; Winz et al., 2023 ). Together, these features highlight the need for future studies to incorporate mixture-based exposure assessment, repeated biomonitoring, exposure-window stratification, and non-linear dose–response modeling. Assessing EDC risk is further complicated by prolonged biological half-lives and extensive latency periods, which can exceed 50 years between initial exposure and clinical manifestation ( Yilmaz et al., 2020 ). Due to their lipophilic nature, EDCs readily accumulate in white adipose tissue ( Francis et al., 2021 ). Biomonitoring studies have detected these compounds in virtually all human biospecimens, including blood, urine, placenta, and fetal cord blood, highlighting the ubiquity of exposure across the life course ( Sabuz Vidal et al., 2021 ). However, individual phenotypic responses to these stressors vary markedly, influenced by a complex interplay of genetic predisposition, occupational factors, underlying comorbidities, and dietary habits. The traditional toxicological paradigm, stating that adverse effects occur only at high doses, increasingly challenged by evidence showing that EDCs can exert profound homeostatic disruption even at picomolar or nanomolar concentrations ( Xu et al., 2025 ). The combined influence of low-dose, chronic, and multi-chemical exposure introduces a level of complexity that traditional single-pollutant models cannot capture ( Yilmaz et al., 2020 ). While preclinical studies have elucidated estrogen receptor-mediated pathways, emerging research emphasizes that EDC-driven genomic instability and epigenetic modifications are equally critical drivers of oncogenesis ( Sun K. et al., 2025 ). To strengthen causal inference in future research, it is imperative to integrate high-precision exposure measurement, longitudinal cohort designs, and multi-omics-based mechanistic validation. Furthermore, practical strategies for exposure mitigation must prioritize vulnerable populations. Evidence indicates higher EDC burdens among low-income communities and occupationally exposed groups (e.g., workers in agriculture, industrial manufacturing, and painting) ( Malits et al., 2022 ). Targeted risk communication, enhanced protective protocols, and the reduction of unnecessary environmental contact are essential to mitigate health inequities. Ultimately, addressing the global EDC threat requires multicenter population studies and standardized analytical methodologies to ensure data comparability. Integrating mixed-exposure frameworks into public health strategies and regulatory policies is paramount, as the chemical mixtures may better reflect real-world exposure conditions and may contribute to EDC-associated disease burden. Another important implication of this integrated framework is that EDC-associated cancer-related effects may be mediated not only by direct endocrine or metabolic disruption, but also by immune remodeling within the TIME. Across different EDC classes, shared pathways such as AhR, NF-κB, ROS, PI3K–AKT–mTOR, AMPK, and PPARs may connect environmental exposure to macrophage polarization, T-cell dysfunction or exhaustion, impaired NK-cell surveillance, cytokine imbalance, and checkpoint-associated immune suppression. However, the strength of evidence varies substantially by compound class and immune endpoint. While immunotoxicity and inflammatory remodeling are supported by experimental and toxicological studies, direct evidence linking EDC exposure to cancer immunotherapy outcomes remains limited and should be regarded as an important area for future investigation. In summary, this review bridges the critical gap between environmental toxicology and clinical oncology by delineating the multifaceted impact of EDCs on cancer progression. Beyond elucidating molecular crosstalk, we provide a translational framework that enhances clinical utility in three pivotal areas: first, the identification of EDC-associated molecular signatures offers a novel avenue for developing precision biomarkers for early cancer screening in high-exposure cohorts; second, the integration of environmental exposure history into oncological risk models enables more accurate risk stratification and the identification of patients predisposed to aggressive phenotypes; and third, the highlight of targeted interventions offers actionable strategies to mitigate EDC-induced therapeutic resistance and immune evasion. Ultimately, these insights empower clinicians to transition from conventional tumor-centric approaches to a more comprehensive, environment-aware paradigm of personalized cancer management.

In tandem with phenotypic switching, tumor cells undergo profound metabolic reprogramming to satisfy the bioenergetic and biosynthetic demands of rapid proliferation ( Cordani et al., 2024 ). Metabolic hubs, specifically the PI3K/Akt/mTOR and AMPK pathways, serve as master regulators of metabolic flux. By modulating the expression and catalytic activity of rate-limiting enzymes, these pathways remodel cellular networks across glucose, lipid, and amino acid metabolism ( Tan et al., 2022 ; Talwar et al., 2023 ; Ambrosini et al., 2020 ; Hoxhaj and Manning, 2020 ). This metabolic plasticity not only supports survival under conditions of hypoxia and nutrient scarcity but also provides the energetic basis for sustained invasion and the acquisition of therapeutic resistance. Within the integrated “EMT–metabolic plasticity” framework, the impact of environmental EDCs manifests as a multi-target and multi-pathway modulation of cellular signaling. EDCs exert toxicity by perturbing hormone synthesis, secretion, and receptor-mediated activity, thereby altering the developmental microenvironment of reproductive and other endocrine-sensitive tissues ( Yilmaz et al., 2020 ). Furthermore, EDCs exert a dual influence on the metabolic ecosystem: systemic metabolic disruption, inducing organism-wide disturbances, such as dysregulated lipid/glucose homeostasis and chronic low-grade inflammation; local tumor remodeling, triggering adaptive metabolic shifts and signaling crosstalk within the tumor and its immediate microenvironment. This “dual-route” mechanism, coupling systemic metabolic dysfunction with localized cellular reprogramming, may contribute to tumor-promoting metabolic states and therapy-related adaptive responses. Importantly, EDC-associated metabolic reprogramming is closely intertwined with immune remodeling. Altered glycolysis, lipid metabolism, mitochondrial function, and redox balance can modify nutrient availability and inflammatory signaling within the TIME. These changes may suppress cytotoxic CD8 + T-cell and NK-cell activity, favor macrophage polarization toward tumor-supportive phenotypes, and promote cytokine networks characterized by IL-6, TNF-α, IL-10, TGF-β, CCL2, and CXCL-family chemokines. In addition, activation of AhR, NF-κB, PI3K–AKT–mTOR, HIF-1α, and ROS-related pathways may contribute to immune checkpoint regulation, including PD-1/PD-L1-associated suppressive signaling. Therefore, EDC-induced endocrine and metabolic perturbations should be interpreted together with TIME remodeling rather than as isolated processes ( Dairkee et al., 2012 ). Since p53 is closely involved in treatment-induced apoptosis and genomic stress responses, BPA-associated p53 disruption may represent a plausible mechanism through which bisphenols influence treatment sensitivity. In parallel, BPA and related bisphenol analogs have been shown to alter nucleotide metabolism, purine and pyrimidine pathways, lipid metabolism, glycolytic intermediates, and glutathione metabolism ( Zhao et al., 2022 ; Liu et al., 2020 ; Ma et al., 2021 ; Huang et al., 2020 ; Zhao C. et al., 2019 ). These metabolic alterations may provide additional support for proliferating or stressed tumor cells under therapeutic pressure. Phthalates and PCBs may influence resistance-related biology primarily through metabolic remodeling and EMT-associated phenotypes, although direct clinical evidence remains limited. Phthalate exposure has been linked to endocrine–metabolic disturbance, lipid metabolic dysregulation, and metabolic contexts that may modify cancer risk, particularly in metabolically vulnerable populations. BPA disrupts systemic metabolic homeostasis primarily by targeting the liver, a central hub for energy balance ( Winz et al., 2023 ). Both BPA and 17β-estradiol modulate the urea and tricarboxylic acid (TCA) cycles, resulting in the elevation of intracellular metabolites such as arginine, creatine, and glutamine ( Cabaton et al., 2018 ). Given that the upregulation of amino acid transport and metabolism, particularly of arginine and glutamine, is a hallmark of malignancies providing essential substrates for nucleotide synthesis and redox maintenance, these BPA-associated metabolic shifts may contribute to a systemic environment that favors tumor-related metabolic adaptation ( Wei et al., 2020 ). Beyond amino acids, BPA perturbs lipid metabolism by altering apolipoprotein profiles ( Cabaton et al., 2018 ). In CD-1 mice, hepatic BPA exposure is associated with the upregulation of Apob and the downregulation of Apoc3 ( Lin et al., 2017 ). Collectively, this simultaneous disruption of lipid and amino acid pathways suggests that BPA establishes a foundational systemic context that supports tumor initiation and subsequent local adaptation. BPA can directly reshape the metabolome within tumor cells. In ER-positive MCF-7 BC cells, BPA exposure significantly accelerates nucleotide metabolism, evidenced by increased levels of precursors such as cytidine triphosphate and uridine diphosphate glucuronic acid ( Zhao et al., 2022 ). Research utilizing a “leave-one-out” mixture analysis confirmed that BPA is a primary driver of purine and pyrimidine metabolic alterations ( Liu et al., 2020 ). Because rapidly proliferating cells require an augmented supply of nucleotides for DNA synthesis, this BPA-mediated enhancement of salvage pathways likely provides the metabolic support necessary to maintain high proliferative rates ( Ma et al., 2021 ). Other bisphenol analogs also demonstrate pro-tumorigenic metabolic effects: BPS disrupts the TCA cycle, purine, and lipid metabolism in MCF-10A cells ( Huang et al., 2020 ); TBBPA/TCBPA alter glycolytic intermediates and glutathione metabolism, perturbing cellular antioxidant systems ( Zhao C. et al., 2019 ); BPF induces shifts in glycerophospholipid degradation and glycolysis-related pathways in vivo ( Zhao et al., 2018 ). The molecular basis of these phenotypic changes resides in the ability of BPA to engage a multi-receptor network, including ERα, ERβ, GPER, membrane-associated ERs, thyroid hormone receptors, and the AR(109). For example, BPA activation of ERβ-mediated ion flux has been proposed as one of the key bases for reduced insulin secretion in pancreatic β cells following BPA exposure ( Villar-Pazos et al., 2017 ). Notably, BPA is also implicated in the acquisition of therapeutic resistance. Evidence suggests that BPA exposure is associated with the inactivation of p53 in human cancer cells, potentially weakening DNA damage responses and apoptotic pathways ( Dairkee et al., 2012 ). By coupling systemic lipid/amino acid disruption with local nucleotide synthesis and the suppression of tumor-suppressor pathways, bisphenols may influence cancer-related metabolic phenotypes and altered treatment sensitivity under specific biological contexts. Direct evidence linking PCBs to tumor metabolic reprogramming remains an emerging field. The quinone-type PCB metabolite, PCB29-pQ, significantly induces the expression of the glucose transporter GLUT1, triggering the GLUT1/integrin β1/Src/FAK signaling cascade, which promotes EMT, extravasation, and metastatic dissemination ( Zhao H. et al., 2019 ). Moreover, inhibiting GLUT1 effectively attenuates the pro-metastatic effects of PCB29-pQ In vivo , underscoring a functional cascade where PCBs remodel nutrient uptake and energy metabolism to confer a migratory and invasive advantage to tumor cells ( Qin et al., 2022 ). Beyond their localized effects within the tumor, PCBs function as systemic metabolic disruptors. They contribute to oncogenic risk by inducing lipid metabolic disorders and promoting chronic conditions such as obesity and type 2 diabetes ( Shan et al., 2020 ). Metabolomic and pathway enrichment analyses reveal that elevated blood PCB concentrations correlate with significant alterations in fatty acid biosynthesis and activation pathways. Notably, these perturbations are amplified when PCB exposure occurs in conjunction with other EDCs, such as DDT and PFAS. This suggests that mixed-exposure scenarios exacerbate disruptions within lipid metabolic networks ( Li et al., 2020 ). Given that these lipophilic EDCs interact with nuclear transcription factors to regulate fatty acid uptake and biosynthesis, their dual roles as “systemic metabolic disruptors” and “local tumor metabolic promoters” likely act additively to foster a pro-carcinogenic environment ( Shan et al., 2020 ). At the population level, EDCs promote metabolic abnormalities by activating shared downstream pathways, which in turn serve as major risk factors for hormone-dependent malignancies. For example, dyslipidemia, a hallmark of systemic metabolic disturbance, provides a pro-inflammatory and nutrient-rich milieu that supports the development of prostate, colon, and pancreatic cancers ( Winz et al., 2023 ). In the context of BC, altered lipid metabolism and elevated circulating free fatty acids have been directly correlated with increased incidence and enhanced tumorigenicity ( Marino et al., 2020 ; Madak-Erdogan et al., 2019 ). Crucially, the exposure window is a decisive factor: EDC exposure during sensitive developmental periods, such as in utero and lactation, can “early-program” the metabolome and mammary architecture. This programming may leave adult mammary tissue more susceptible to malignant transformation by optimizing metabolic supply and hormonal responsiveness for future tumor growth ( Winz et al., 2023 ). In summary, PCB-related research highlights a multifaceted oncogenic model where PCBs couple intra-tumoral metabolic remodeling with systemic dysregulation, particularly when exposure occurs during critical developmental windows. Although different classes of EDCs vary substantially in chemical structure, exposure route, persistence, and tissue distribution, accumulating evidence indicates that their cancer-related effects may converge on a set of shared molecular and cellular hubs. These hubs provide a mechanistic bridge between chemical-specific observations and broader cancer phenotypes, including endocrine dysregulation, metabolic reprogramming, immune remodeling, epithelial–mesenchymal transition (EMT), tumor progression, and therapy-related adaptation. At the receptor level, several EDCs interfere with nuclear and membrane-associated hormone signaling pathways, particularly estrogen receptors (ERs), androgen receptor (AR), G protein-coupled estrogen receptor (GPER), aryl hydrocarbon receptor (AhR), and peroxisome proliferator-activated receptors (PPARs). Bisphenols primarily affect ER-, AR-, and GPER-mediated signaling, whereas dioxins, PCBs, and heavy metals are more closely associated with AhR activation and oxidative stress-related transcriptional responses. PFAS, phthalates, and PCBs may also interact with PPAR-related pathways, thereby linking endocrine disruption to lipid metabolism, adipogenesis, and systemic metabolic dysfunction. These receptor-level perturbations can further propagate to downstream signaling cascades, including PI3K–AKT–mTOR, AMPK, MAPK, and NF-κB pathways. Beyond receptor signaling, oxidative stress and mitochondrial dysfunction represent important convergent mechanisms across multiple EDC classes. Reactive oxygen species (ROS) generation may contribute to DNA damage responses, inflammatory signaling, metabolic rewiring, and apoptosis resistance. In parallel, altered mitochondrial function may shift cellular energy metabolism toward glycolysis, lipid metabolic remodeling, and adaptive survival programs. These metabolic changes can influence not only tumor-cell proliferation but also the tumor immune microenvironment (TIME), as nutrient competition, altered metabolite availability, and inflammatory mediators may collectively support immune suppression and impaired antitumor surveillance. Importantly, these mechanisms should not be viewed as isolated linear pathways. Instead, EDC-associated endocrine disruption, oxidative stress, metabolic reprogramming, EMT, immune remodeling, and therapeutic adaptation are likely to form an interconnected network. For example, ER/GPER and PI3K–AKT signaling may promote proliferative and survival phenotypes; AhR and NF-κB activation may link environmental exposure to inflammatory and immunosuppressive responses; AMPK and mitochondrial dysfunction may reshape energy metabolism under stress conditions; and EMT may further interact with metabolic plasticity and drug resistance. Therefore, the carcinogenic relevance of EDCs may be better understood through a multi-hub framework rather than through single-compound or single-pathway models. To clarify these shared mechanisms, we summarized the major convergent molecular hubs across representative EDC classes in Table 1 . This integrated framework highlights how diverse environmental exposures may influence cancer-related phenotypes through overlapping receptor, metabolic, inflammatory, and immune-regulatory pathways. We summarized the major exposure sources, cancer associations, receptor and signaling hubs, immune-related effects, and metabolic alterations for representative EDC classes in Table 2 . This integrated summary highlights that structurally diverse EDCs do not act through completely isolated mechanisms. Instead, they frequently converge on shared endocrine, inflammatory, immune-regulatory, and metabolic pathways, including ER/AR/GPER, AhR, PPARs, PI3K–AKT–mTOR, AMPK, NF-κB, ROS, mitochondrial dysfunction, glycolysis, lipid metabolism, EMT, and immune suppression. Shared mechanistic hubs linking EDC exposure to cancer-related phenotypes. Summary of major EDC classes, exposure sources, cancer associations, mechanistic hubs, immune/metabolic effects, and evidence levels.