Chronic inflammation promotes carcinogenesis by inducing variants and epigenetic alterations in key regulatory genes, disrupting normal cellular growth control ( Figure 2 ) (34). Many basic experiments have corroborated these results. Chronic inflammation also drives oxidative stress and excessive lipid peroxidation, leading to elevated oxidase activity and increased production of reactive oxygen species (ROS) and reactive nitrogen species (RNS). These reactive intermediates cause DNA and mitochondrial damage, impair repair pathways, and inactivate tumor suppressor genes, thereby facilitating tumor development (35).

Inflammatory cytokines contribute to cancer development by inhibiting apoptosis, inducing angiogenesis, and disrupting normal inflammatory signaling (36). Chronic inflammation is marked by immune cell infiltration, which drives cytokine release and stress protein production, forming a microenvironment conducive to cancer development (37–39).

Key inflammatory mediators include proteases, arachidonic acid, cyclooxygenase, IL-4, IL-7, NF-κB, TNF-α, IFN-α, IL-1β, IL-8, and coagulation factors (40–42). Major stress proteins involved are heat shock proteins (HSPs) and glucose-regulated proteins (GRPs). Together, these molecules support tumor cell proliferation, survival, and metastasis, underpinning cancer initiation and progression (43–45).

The tumor suppressor gene p53 plays a central role in colitis-associated cancer (CAC), with early dysplastic changes commonly detected in colitis biopsies (46). These findings have been corroborated by numerous clinical studies. A meta-analysis of 19 studies by Lu et al. (47) reported a significantly higher p53 expression in UC patients compared to normal controls (OR: 3.14, p = 0.001), with higher expression in patients with dysplasia compared to those without dysplasia (OR: 10.76, p < 0.001). Although less pronounced, a significant difference in p53 expression was observed between UC cancer patients and patients with dysplasia (OR: 1.69, p = 0.035). Phosphoinositide 3-kinase (PI3K), a key signaling mediator in tumorigenesis, enhances cell migration, proliferation, and survival. Colon biopsies from UC and CAC patients revealed PI3K pathway activation, particularly involving the IL23R rs10889677 variant (c.309C>A), which was highly prevalent. Alterations in interleukin-12 receptor beta 1 (IL12Rβ1) were also detected in 20% of samples (48, 49). Other inflammation-driven carcinogenic pathways implicated in UC include Toll-like receptors, cyclooxygenases, carbonic anhydrases 2/9, and microRNAs (miRNAs), all contributing to neoplastic transformation (50–53). These findings have been obtained from clinical studies.

Regulatory T cells (Tregs) suppress excessive immune activation and self-inflicted tissue injury (54). However, Tregs exhibit plasticity, converting into Th17 cells that exacerbate inflammation. In UC, Tregs can paradoxically produce IL-1 and IL-6, serving as effector cells that contribute to UC and CAC pathogenesis (55, 56). Another mechanism involves neutrophil extracellular traps (NETs), formed via NETosis—a distinct cell death pathway triggered by pathogens, immune complexes, and ROS. This process involves the activation of NADPH oxidase, myeloperoxidase (MPO), and neutrophil elastase (NE), leading to chromatin decondensation and NET formation. UC patients show elevated levels of peptidyl arginine deiminase 4 (PAD4), MPO, and NE in the colonic mucosa, suggesting the important role of NETs in UC-related inflammation (57). Additionally, autophagy and macrophage-mediated immune regulation have been linked to the transition from chronic colitis to colon cancer (58).

Gut microbiota alterations contribute significantly to colitis-associated carcinogenesis. Probiotic modulation using Clostridium butyricum (CB) and Akkermansia muciniphila (AKK) reduced weight loss in a dextran sodium sulfate (DSS)-induced IBD mouse model. Furthermore, in the azoxymethane (AOM)/DSS-induced CAC mouse model, the combined probiotic treatment reduced tumor burden and Ki67 expression (a proliferation marker). Treatment also increased Caspase-3 activity (an apoptosis marker) and decreased CD8+ T cell and macrophage infiltration, enhancing anti-PD-L1 therapy efficacy (59). Xu et al. (60) identified Achromobacter pulmonis (A. pulmonis), isolated from mesenteric adipose tissue of CD patients, as a colitis-aggravating bacterium in mice. Its type III secretion system (T3SS) gene cluster induced macrophage and epithelial cell necrosis via the effector protein AopD, independent of caspase activation. Clinical studies have shown similar findings. Fecal samples from CD patients showed a significant abundance of Achromobacter and T3SS core genes compared to healthy individuals and patients with UC/CRC. Saussurea costus (SC) also showed therapeutic potential in a UC mouse model, alleviating weight loss, fecal occult blood, and colon shortening. SC restored colonic architecture, reduced inflammation, and modulated the gut microbiota, decreasing the abundance of harmful bacteria, such as Proteobacteria, and increasing beneficial bacteria, including Lactobacillus (lactic acid bacteria) and Firmicutes. This shift in microbial community structure suggested that the therapeutic effects of SC may be partly attributed to its ability to restore gut microbiota homeostasis (61).

Immunomodulators (e.g., azathioprine [AZA], 6-mercaptopurine) and biologics, particularly TNF-α inhibitors, are cornerstone treatments for pediatric IBD (62–64). However, prolonged use of these medications may increase the risk of malignant tumors ( Figure 2 ). Several results have been obtained from clinical studies.

AZA, an imidazole derivative of 6-mercaptopurine, suppresses nucleic acid biosynthesis and cell proliferation, potentially causing DNA damage. It is widely used for long-term IBD maintenance therapy, as it reduces disease activity, steroid dependence, relapse rates, and postoperative recurrence (65–67). However, the association between long-term AZA use and cancer risk remains debated. The following studies link AZA to fatal malignancies, including colorectal, skin, and hematologic cancers (68). A meta-analysis of 18 studies involving adult populations found that AZA significantly increases lymphoma risk, particularly in current users, with males having a higher risk than females. Thus, due caution should be exercised during long-term AZA treatment in elderly patients (>50 years) and young males (<30 years). Notably, 56% of lymphoma cases were EBV-positive, implicating immunosuppression-induced EBV reactivation as a possible mechanism (69). In contrast, a single-center retrospective study of 1,374 pediatric and young adult IBD patients identified only two lymphoma cases over 6,624 patient-years, both in males treated with thiopurines, but not biologics. No significant increase in lymphoma risk was observed in the subgroup of pediatric patients treated with thiopurine drugs (70). To some extent, lymphoma risk may reflect underlying IBD severity, with treatment benefits potentially outweighing the disease risks. Another meta-analysis of 27 studies (95,397 patients) found that AZA use was associated with a decreased risk of CRC. The analysis revealed a significant risk reduction, with case-control studies showing a 51% decrease in risk, and cohort studies revealing a slight 4% risk reduction. These data are derived from adult populations. Notably, AZA exhibited a chemopreventive effect in high-risk CRC patients with a longer disease course (>8 years). However, no protective effect was observed in patients with extensive colitis or concomitant PSC (71). Nonetheless, another meta-analysis revealed that AZA did not prevent progression from mild atypical dysplasia to severe atypical dysplasia or CRC in IBD patients (72). Since most of the present evidence is based on studies involving adult cohorts, more robust research is required to better characterize the carcinogenic effects of thiopurine drugs in pediatric populations.

TNF-α-inhibitors, such as infliximab and adalimumab, have revolutionized IBD treatment, enabling the achievement of clinical remission in patients with CD and UC (73, 74). These drugs neutralize pro-inflammatory TNF-α molecules, modulate intestinal immune responses, and promote mucosal healing (75). However, their long-term safety—particularly the potential malignancy risk in pediatric patients—remains a concern. A 2008 U.S. FDA report documented malignancies in children who received anti-TNF therapy for immune-related diseases (including IBD), prompting reduced AZA use in pediatric patients. Among 31 reported pediatric malignancy cases post-infliximab, 24 involved IBD patients. Notably, nine developed fatal HSTCL, while others developed NHL, Hodgkin lymphoma, or leukemia. Most IBD patients (20 of 24 patients) had received thiopurines; only four received methotrexate in combination (76). In contrast, basic research suggests that infliximab may reduce cancer risk. In a DSS-induced colitis mouse model, early intervention with infliximab significantly reduced CRC incidence from 75–80% to 16.7% (77). Supporting this, a 20-year U.S. cohort study (1999–2020) found that TNF antagonist use was associated with a significantly lower risk of CRC in IBD patients (adjusted OR: 0.69 for CD; 0.78 for UC) (78). A recent meta-analysis of 55 studies (57,518 patients) found no significant increase in overall cancer risk with TNF-α inhibitors—including adalimumab, infliximab, etanercept, certolizumab, and golimumab—in both interventional and observational studies (79). Although a trend toward increased risk emerged with long-term follow-up, most studies had short follow-up periods, highlighting the need for high-quality, long-term prospective studies to better assess malignancy risk and optimize adverse event monitoring (79).

Environmental factors, such as diet, lifestyle, and air pollution, have also been implicated in the development of IBD ( Figure 2 ). Long-term high-fat diet (HFD) consumption disrupts intestinal barrier homeostasis in mice, accelerating CRC progression by promoting a chronic inflammatory microenvironment (80). HFD-induced inflammation not only drives malignant transformation but may also create a self-sustaining pro-cancer loop. Animal experiments have demonstrated that prolonged HFD exposure induces low-grade chronic intestinal inflammation, impairs mucosal barrier function, and increases IBD risk (81). Epidemiological data further support a positive correlation between excessive fat intake and CAC incidence. Experimental models to elucidate the molecular pathways linking diet and CAC remain limited. Activation of the STAT3 transcription factor plays a crucial role in CAC by upregulating anti-apoptotic proteins like Bcl-2, correlating with the clinical and pathological features of CAC (82). Clinical studies have revealed increased levels of phosphorylated STAT3 (pSTAT3) in the intestinal epithelial cells of patients with CAC (83). While the mechanisms by which HFD exacerbates CRC via STAT3 remain unclear, cross-disease evidence suggests STAT3 signaling is central to HFD-induced tumorigenesis. Specifically, the amplification of STAT3-mediated pro-cancer signaling cascades warrants further exploration. Furthermore, HFDs contribute to CAC by altering gut microbiota’s butyrate metabolism. Research has demonstrated that HFDs reduce the abundance of butyrate-producing bacteria (e.g., Clostridiaceae), and lower intestinal butyrate levels, correlating with increased polyp formation (p = 0.007) and reduced ZO-1 expression (p = 0.004), a marker of epithelial barrier integrity. Notably, these carcinogenic effects were reversed by broad-spectrum antibiotics or butyrate supplementation, suggesting the microbiota’s role in CAC pathogenesis and supporting dietary or microbial interventions in high-risk IBD patients (84). A recent preclinical study demonstrated the anti-cancer properties of Bacteroides plebeius, a gut symbiont that degrades algal polysaccharides (85). In AOM/DSS-induced CRC mice, oral administration of B. plebeius reduced tumor number and size by 50% (p < 0.01), with less inflammatory infiltration in colon tissues. The proposed mechanism involves modulation of gut microbiota (increasing beneficial bacteria and decreasing pathogenic bacteria) and increased production of anti-cancer metabolites (e.g., propionate and ursodeoxycholic acid [UDCA]) (85).

The increasing incidence of IBD in newly industrialized countries is linked to environmental factors, particularly air pollution. Mendelian randomization analysis identified PM2.5 as a significant UC risk factor (86). A UK Bio-bank study of 453,199 individuals found that increased exposure to nitrogen oxides (Nox), nitrogen dioxide (NO₂), PM2.5, and a composite pollution score increased UC risk by 20–26% per each interquartile range (IQR) increment, with stronger risk in populations with high genetic risk, unhealthy diets, smoking, obesity, or alcohol use. Epigenetic analysis revealed significant associations between UC risk and methylation changes in the CXCR2 gene (chemokine receptor), and the MHC III region (e.g., AGPAT1 and DDAH2). These changes were validated in colonic tissues and correlated with gene expression regulation (87). The latter two genes play a crucial role in colitis and CAC (88).

The incidence of dysplasia and CRC in pediatric patients with UC has been underreported, resulting in the lack of data to inform a defined CRC screening protocol. Moreover, discrepancies exist in screening recommendations among various guidelines. The ECCO-ESPGHAN guidelines recommend initiating endoscopic surveillance at 8-10 years after disease onset, based on individual risk factors (89), using chromoendoscopy performed by experienced gastroenterologists. While optimal surveillance intervals remain undefined, ECCO-ESPGHAN recommends universal screening at 10 years after disease onset, whereas Dutch guidelines recommend screening only in children with extensive colitis (89, 90). Due to the scarcity of pediatric data, CRC surveillance guidelines for children with UC are extrapolated from adult studies. In adults, routine surveillance is not recommended for ulcerative proctitis, given the comparable CRC risk to the general population (91, 92). However, pediatric guidelines remain inconsistent due to limited evidence. PSC is an established independent risk factor for dysplasia and CRC in children with UC. Consequently, both pediatric and adult UC guidelines recommend annual or biennial surveillance colonoscopies starting from the diagnosis of PSC ( Figure 3 ) (89–91).

Chromoendoscopy is the preferred surveillance method per guidelines, but limited access and expertise may hinder its use. As alternatives, the European guidelines recommend high-definition or white-light endoscopy combined with random biopsies as a suitable alternative. Furthermore, the Dutch adult IBD guidelines recommend white-light endoscopy with targeted biopsies (89, 91). Given technical limitations in pediatric settings, collaboration with experienced gastroenterologists is recommended. For high-risk groups, such as those with VEO-IBD or concurrent PSC, earlier and more frequent surveillance may be warranted.

Given the elevated risk of skin cancer in pediatric IBD patients, especially those who have received AZA, anti-TNF therapies, or combination therapies, some researchers have recommended lifelong dermatological screening. Given the scarcity of data on the pediatric population, adult guidelines are used as a reference. The primary focus should be screening for basal cell carcinoma, melanoma, and non-melanoma skin cancers, with emphasis on ultraviolet (UV) protection (e.g., sunscreen use, minimizing UV exposure) ( Figure 3 ) (21). Danish researchers suggest incorporating skin cancer surveillance into standard care, particularly for male patients. However, the optimal frequency and methods for screening remain undefined (22, 33).

Adolescent males and patients on multiple immunosuppressants (e.g., AZA + anti-TNF) require close monitoring for lymphoma. Due to limited data on children, guidelines for adult populations are referenced. Persistent fever, lymphadenopathy, hepatosplenomegaly, or cytopenia warrant evaluation for lymphoma, with the diagnosis confirmed through imaging (e.g., computed tomography [CT]) and bone marrow biopsy ( Figure 3 ) (27). EBV serology (IgM/IgG) should be assessed before and during treatment, as AZA may heighten lymphoma risk in EBV-positive patients (20, 26). For EBV-negative patients, EBV screening is recommended before initiating immunosuppressive therapy to assess lymphoma risk (26). Although no standardized protocol exists, regular clinical assessments are recommended every 6-12 months, with shorter intervals for high-risk groups.