Expression analysis based on a dataset indicated significantly elevated expression levels of IL-1β in esophageal cancer cases compared to normal samples[6]. A positive immunohistochemistry score for IL-1β correlated with a diminished response to neoadjuvant therapy and poorer overall survival among patients with esophageal squamous cell carcinoma (ESCC)[7]. In the context of ESCC, investigations revealed that the overexpression of IL-1RA, conversely, curtailed the proliferation, migration, and lymphangiogenesis of ESCC cells. This effect was attributed to the downregulation of vascular endothelial growth factor-C and matrix metalloproteinase 9 (MMP-9). Downregulation of IL-1RA was also observed in esophageal carcinomas[8]. Furthermore, in vivo assessments demonstrated a significant reduction in the growth rate of ESCC upon IL-1RA overexpression[9]. In another in vivo model, IL-1β transgenic mice exhibited inflammation-driven, age-dependent progression toward malignancy of the esophagus, characterized by squamous epithelial hyperplasia, dysplasia, and finally ESCC. Notably, this inflammation-based progression occurred independently of the gut microbiome[10]. Within the transgenic L2-IL1B mice cohort subjected to a high-fat diet to promote inflammation-based progressive esophageal adenocarcinoma[11], IL-1R antagonist and anti-inflammatory agent administration significantly diminished inflammatory scores and also led to a reduction in metaplasia and dysplasia scores in L2-IL1B mice exposed to a high-fat diet. All these findings emphasize the significant roles of IL-1β as a linking cytokine for chronic inflammation and esophageal cancer in both histological subtypes of squamous cell carcinoma and adenocarcinoma.

IL-1β exerts a multifaceted influence on the development and progression of gastric cancer, primarily through its capacity to inhibit gastric acid secretion, induce epigenetic alterations, facilitate angiogenesis, attract adhesive factors, and release various inflammatory mediators[12]. A meta-analysis revealed an association between IL-1B−511C/T polymorphisms and susceptibility to an intestinal subtype of gastric adenocarcinoma[13]. Within gastric carcinoma cell lines, such as BGC-823, IL-1β was observed to upregulate retinoid X receptors via the activation of NF-κB signaling pathways[14]. Additionally, IL-1β enhanced NF-κB activation, MMP-9 expression, and invasive capabilities of gastric cancer cells[15]. The gastric-specific overexpression of human IL-1β in transgenic mice was demonstrated to be sufficient for the progression of gastric dysplasia to cancer. Moreover, the activation of NF-κB in myeloid-derived suppressor cells (MDSCs) was significantly associated with cancer development. Notably, blockade by IL-1RA significantly impeded histological progression and diminished MDSC recruitment[16]. Examining the tumor microenvironment, the majority of tumor-associated macrophages (TAMs) exhibit expression of proinflammatory cytokine/chemokine genes, including IL1B, CCL2, CCL3, and CCL20. IL-1β and its decoy receptor IL1-R2 are also the most abundant cytokine–receptor pair interaction between TAMs and tumor cells. This suggests a potential mechanism where tumor cells can be inhibited by targeting IL-1β-mediated proinflammatory signaling within the tumor microenvironment[17].

Polymorphic variations within the IL1B gene, concomitant with heightened levels of IL-1β, have been significantly associated with an augmented susceptibility to the development of colon cancer[18]. Conversely, single-nucleotide polymorphisms associated with the expression of IL-1RA have been linked to the enhanced survival of patients with colorectal cancer (CRC)[19]. A meta-analysis demonstrated that IL-1α rs3783553, IL-1β + 31C/T, IL-1β + 511C/T, and IL-1RN VNTR are critical genes for CRC susceptibility[20]. Noteworthy, serum levels of IL-1β exhibited a significant upregulation in patients with CRC when compared to healthy controls[21]. The addition of IL-1β to the culture medium was found to significantly augment the sphere-forming capability and invasive potential of colon cancer cell lines[22] induction by IL-1β and was also associated with an increased expression of the epithelial-mesenchymal transition activator, Zinc finger E-box-binding homeobox 1, in IL-1β-induced spheres. In colonic CAFs, IL-1β initiated pro-tumorigenic signaling, leading to the nuclear translocation of NK-κB p65 and subsequent enhancement of tumor growth in vitro[23]. Targeting basal IL-1β crosstalk between CAFs and colorectal tumor cells may also inhibit the pro-tumorigenic function of CAFs. IL-1β has also been shown to have pro-tumorigenic effects via activation of NF-κB and miR-181a[24]. IL-1β activated NF-κB and miR-181a, which further repressed phosphatase and tensin homolog, a ubiquitous tumor-suppressor gene implicated in various solid tumors and immune responses[25-27]. Conversely, the anti-tumorigenic effect of IL-1β has also been reported in colon cancer. Increased tumor burden was correlated with attenuated levels of IL-1β and IL-18 at the tumor sites[28]. A protective role of IL-1β was demonstrated in mouse models of chemically induced colitis and colon cancer[29]. Two variants of the IL1B gene, including rs1143623 and rs1143634 polymorphisms, were associated with decreased risk, more favorable clinical features, and better overall survival of CRC than the wild type[30]. Different study models have resulted in diverse effects of IL-1β in CRC development and progression. Thus, the roles of IL-1β remain unclear in CRC and need further investigation.

The examination of allele frequencies pertaining to IL-1B-511 revealed significant elevations among individuals afflicted with hepatitis B virus-associated hepatocellular carcinoma (HCC) compared to healthy controls[31]. Notably, within hepatitis C-infected individuals, the IL-1B-511 genotype T/T emerged as a risk factor for HCC. Polymorphic variations within the IL-1B-511 genetic locus were raised as possible risk factors for HCC development[32]. Mechanistically, miR-4756 inhibition reversed the effects induced by circUBAP2 silencing on the IL-17 and IL-1β levels and HCC cell migration[33]. Orthotopic liver tumor models and RNA-sequencing demonstrated a pivotal role for pulmonary IL-1β in creating a permissive lung pre-metastatic niche via enhancing MMP-9 expression and recruiting myeloid cells, thus promoting pulmonary metastasis of HCC[34]. In contrast, the hepatitis B virus modulated liver macrophage function to favor the establishment and likely maintenance of infection. It impaired the production of IL-1β, playing roles as antiviral cytokines, while promoting that of IL-10 in the microenvironment[35]. An in vitro model revealed that anakinra, an IL-1R1 antagonist, reversed IL-1β-promoted HCC metastasis[36]. IL-1β can promote TAMs and MDSCs infiltration via induction of solute carrier family 7-member 11 overexpression, thus up-regulating programmed death-ligand 1 and colony-stimulating factor 1 through the α-ketoglutarate/hypoxia-inducible factor 1 subunit alpha axis. These result in homeobox protein Hox-C10 overexpression and exacerbate HCC metastasis through the upregulation of phosphoinositide-dependent kinase-1 and vasodilator-stimulated phosphoprotein[37]. IL-1β/IRAK-1 inflammatory signaling can also promote an oncoprotein ankyrin, which is activated during hepatocarcinogenesis[38]. In summary, although IL-1β exerted anti-viral effects on the carcinogenic virus hepatitis B and C, IL-1β then turned out to be a “friend” for HCC, promoting growth and metastasis and avoiding the effects of anti-tumor immunity when hepatocytes turn malignant.

IL-1β expression in pancreatic tumors was associated with shorter survival of patients with pancreatic ductal adenocarcinoma (PDAC)[39]. Physical proximity with IL-1β⁺ TAMs was associated with inflammatory reprogramming and acquisition of pathogenic properties by a subset of PDAC cells[40]. Inhibiting IL-1β activity caused TAM reprogramming and antagonized tumor cell inflammation, leading to PDAC control in vivo. Tumor cell-derived IL-1β regulated an immune-modulatory program that supported pancreatic tumorigenesis[41]. IL-1β also served as a key cytokine that activated IRAK4 in pancreatic CAF[42,43]. Targeting IRAK4 or IL-1β thus rendered PDAC less fibrotic and more sensitive to gemcitabine in vivo.

IL-1β expression was significantly upregulated in gallbladder cancer (GBC) cases as compared with non-malignant cholelithiasis controls[44]. The study also showed that levels of IL-6, IL-1β, and IL-23 were significantly higher in GBC patients, whereas transforming growth factor-β was lower compared with healthy individuals[45]. In a north Indian population, the haplotype 1/C of IL1B was found to confer a significantly enhanced risk of GBC in patients with gallstones[46]. Exogenous IL-1β promoted the proliferation of GBC-SD and SGC996 cells in vitro and in vivo and also promoted migration in vitro via TWIST activation[47]. To date, most studies in GBC point toward the roles of IL-1β as a pro-tumorigenic cytokine; however, studies on the roles and clinical significance of IL-1R are still lacking.

A genetic polymorphism study revealed that the IL-1B +3954 C/C genotype was associated with a shorter overall survival in patients with resected intrahepatic cholangiocarcinoma, as determined by both univariable and multivariable analyses. The IL-1B +3954 polymorphism was also associated with shorter disease-free survival[48]. Further, monocytes from patients with primary sclerosing cholangitis, a condition most commonly linked to bile duct cancer[49], produced significantly more IL-1β and IL-6[50]. However, the roles of IL-1β in bile duct cancer progression and their underlying mechanisms remain under-investigated. This is still the missing piece of the jigsaw in the study of IL-1β’s effects on the tumor biology of GI cancers.