Editorial: Interplay between environmental drivers and genetic or epigenetic predispositions on gastrointestinal cancer evolution

Recent studies in this special research Topic have provided key evidence: from the global disease burden increase caused by high BMI, to the carcinogenic effects of epigeneOc genes such as SMYD2 and BTBD19, to the adaptaOon of the tumor microenvironment mediated by the hypoxia-TRIM21-ID1 axis, and the remodeling of the tumor microenvironment and promoOon of immune escape in the TME by the metabolic products of the intesOnal microbiota. These studies collecOvely reveal that cancer is a systems-level process driven by coordinated interacOons between geneOc, epigeneOc, and environmental factors. In gastrointesOnal malignancies, this mulO-layered framework is parOcularly evident: geneOc alteraOons provide the baseline oncogenic potenOal, epigeneOc regulaOon governs dynamic shi`s in cellular states, and environmental pressures determine the selecOve forces that shape tumor iniOaOon and progression.While the geneOc basis of cancer lies in driver mutaOons and clonal selecOon, mutaOoncentric models alone cannot well explain carcinogenesis as well as clinical heterogeneity. EpigeneOc regulaOon provides a crucial complementary mechanism, controlling gene expression without altering the DNA sequences and structures, thereby reshaping cell fate [4]. Wang et al demonstrated that the histone methyltransferase SMYD2 is significantly upregulated and promotes cell proliferaOon, migraOon, and immune evasion via mulOple oncogenic pathways [5]. SMYD2 methylates and suppresses tumor suppressors such as p53 and RB, while acOvaOng PI3K-AKT and STAT3 signaling, thereby enhancing tumor growth and drug resistance. This highlights the role of epigeneOc control during the early stages of carcinogenesis. Yang et al idenOfied BTBD19, a member of the BTB/POZ-domain family, as a promoter of tumor progression through modulaOon of immune infiltraOon and inflammaOon-related pathways. Its overexpression correlates with poor prognosis, suggesOng potenOal as a prognosOc biomarker. In summary, genomic mutaOons shape the foundaOon of cancer occurrence, while epigeneOc modificaOons determine how this nature is acOvated or suppressed in different microenvironments. Together, they consOtute the "intrinsic driving force system" of gastrointesOnal cancer evoluOon.The GI tract, constantly exposed to environmental sOmuli, is profoundly influenced by metabolic and inflammatory signals [6; 7]. Obesity, hypoxia, and metabolic reprogramming not only induce DNA damage but also modulate immune and metabolic pathways that drive malignant progression. Yao et al analyzed Global Burden of Disease 2021 data (1990-2021) and revealed a steady rise in obesity-associated colorectal, liver, and pancreaOc cancers, with an esOmated annual percent change exceeding 4% for pancreaOc cancer. Although high-SDI regions achieve beoer overall cancer management, obesity remains a major risk factor. These findings highlight the global epidemiological impact of metabolic stress on GI cancer and its relevance for public health intervenOons. Cheng et al further elucidated a hypoxiamediated mechanism in pancreaOc ductal adenocarcinoma (PDAC). Hypoxia inhibits the E3 ubiquiOn ligase TRIM21, stabilizing ID1 (Inhibitor of DifferenOaOon 1), thereby promoOng epithelial-mesenchymal transiOon, invasiveness, and chemoresistance. The hypoxia-TRIM21-ID1 axis represents a pivotal adapOve pathway and a potenOal therapeuOc target in the tumor microenvironment. Clinically, such interacOons explain diverse pathophysiological phenomena. For instance, Peng et al reported synchronous primary liver and lung cancers potenOally arising from shared geneOc predisposiOon, environmental carcinogens, or immune dysfuncOon. Similarly, BTBD19-associated immune infiltraOon in colorectal cancer exemplifies bidirecOonal regulaOon between gene expression and tumor immunoecology. Guo et al provides an in-depth analysis of metabolic reprogramming in Colorectal Cancer CRC and links it to the co-metabolism of the gut microbiota, revealing a complex path from pathogenesis to precision therapies. IntegraOng these findings enables a holisOc understanding of GI cancer as both a geneOc and environmental disease.The collecOve evidence underscores that GI tumorigenesis is driven by the interplay of geneOc, epigeneOc, and environmental determinants.• EpigeneOc regulaOon: SMYD2 acOvates mulOple oncogenic cascades; BTBD19 modulates immune and inflammatory pathways to promote tumor growth.• Environmental influence: Obesity, microenvironmental hypoxia, and gut microbial metabolites can all influence tumor development.• IntegraOve suscepObility: Co-occurrence of mulOple primary malignancies indicates shared risk determinants.With advances in mulO-omics and AI technologies, integraOng geneOc, epigeneOc, and environmental data now enables a more comprehensive understanding of tumors. Yet key challenges remain, and future research should prioriOze the following direcOons:1. Mul4-omics integra4on: Combine genomic, epigenomic, and metabolomic data to construct individualized risk networks for precise predicOon of disease progression and therapeuOc response.2. Microenvironment Model Construc4on: Establish GI cancer organoid or microfluidic chip models that incorporate the microbiota to simulate the dynamic feedback loops in vivo for drug screening and mechanisOc validaOon.3. Epigene4c pharmacology: Develop small molecules targeOng regulators such as SMYD2 to reprogram gene expression, and explore combinaOon strategies with gene-targeted and immunotherapies.4. AI-driven preven4on: Apply arOficial intelligence to idenOfy high-risk paoerns and enable early screening and lifestyle intervenOons.Given the worldwide rise of obesity and metabolic disorders, cross-regional cooperaOon and public health iniOaOves are essenOal.GI cancers arise from the coordinated influence of intrinsic and extrinsic pathogenic forces. Intrinsic drivers including geneOc mutaOons and epigeneOc regulators such as SMYD2 and BTBD19 establish the molecular foundaOon and funcOonal plasOcity of malignant evoluOon.In parallel, extrinsic pressures such as high BMI-associated metabolic stress, gut microbiotaderived metabolites, hypoxia-induced microenvironmental adaptaOon, and the complex interplay of environmental exposures reflected in synchronous primary liver and lung cancers collecOvely shape the selecOve landscape that directs tumor progression. Together, these converging insights support a systems-level model in which GI cancer evoluOon emerges from the dynamic integraOon of intrinsic molecular programs and extrinsic ecological forces, offering mechanisOc targets for precision therapies and informing prevenOve strategies to miOgate the growing global burden of gastrointesOnal malignancies.