In 1863, Rudolf Virchow first proposed the connection between inflammation and cancer, suggesting that certain stimuli, along with the tissue damage and inflammation they induce, can drive cell proliferation (1, 2). The inflammatory cells and cytokines present in the TME play a crucial role in promoting tumor growth, metastasis, and modulating immune responses (3). This concept has evolved over time, and decades of research have provided further validation of this link. Chronic inflammation is considered a marker of cancer (4). Mutations contribute to tumorigenesis; however, in the majority of cases (>90%), cancer development is closely linked to chronic inflammation in some form (5).

The relationship between inflammation and tumorigenesis is both complex and deeply interconnected, with chronic inflammation widely regarded as a key factor driving tumor initiation and progression across various cancers. Inflammatory processes, whether infectious—such as H. pylori-induced gastritis (6) or hepatitis B virus-related chronic hepatitis (7)—or non-infectious (8), including autoimmune diseases and chronic tissue damage caused by environmental factors, contribute to tumorigenesis through multifaceted mechanisms (9–12). Chronic inflammation is often characterized by repeated cycles of tissue injury and repair, leading to accelerated cell proliferation, genetic mutation accumulation, disrupted signaling pathways, and diminished immune surveillance, collectively creating a conducive environment for tumor development (9, 13).

In the context of chronic inflammation, inflammatory cells such as macrophages, neutrophils, and lymphocytes release significant amounts of pro-inflammatory cytokines (e.g., IL-6, TNF-α, IL-1β), chemokines, and reactive oxygen species (ROS) or reactive nitrogen species (RNS). These mediators not only induce direct DNA damage (14) but also lead to epigenetic alterations (15, 16) that silence tumor suppressor genes or activate oncogenes. Additionally, pro-inflammatory signals activate critical intracellular pathways such as NF-κB and STAT3, which drive abnormal cell proliferation, inhibit apoptosis, and enhance the invasive and metastatic capabilities of cells (17, 18). Accumulated ROS and RNS further impair DNA repair mechanisms, heightening genomic instability and fostering conditions that facilitate the emergence of cancer cells (19, 20).

Beyond cellular effects, inflammation profoundly influences tumorigenesis by shaping the TME (21). Chronic inflammation drives ECM remodeling paving the way for tumor cell invasion and metastasis (22). Furthermore, pro-angiogenic factors like VEGF (23) secreted within the inflammatory milieu significantly promote angiogenesis, supplying tumors with essential nutrients and oxygen while enabling cancer cells to enter the circulatory system (22, 24). Chronic inflammation also weakens immune surveillance. For instance, TAMs (25) and MDSCs (26), which accumulate in inflammatory conditions, secrete immunosuppressive cytokine that dampen the activity of effector T cells, thereby aiding tumor cells in evading immune responses.

The effects of inflammation on tumorigenesis vary across tissue types and inflammation forms. Chronic inflammation is notably linked to specific cancers, such as colorectal cancer associated with chronic ulcerative colitis (27) and hepatocellular carcinoma linked to chronic hepatitis (28). Compared to acute inflammation, which may transiently activate immune defenses, chronic inflammation exerts more subtle yet persistent effects, including genomic instability, localized immune suppression, and profound alterations to the TME, thereby amplifying tumorigenic potential.In fact, not all chronic inflammatory diseases increase the risk of cancer. Some of these diseases, such as psoriasis, can even reduce the risk of cancer (29).

In conclusion, inflammation serves as a “double-edged sword” in tumorigenesis. While acute inflammation may bolster immune surveillance and eliminate abnormal cells, chronic inflammation promotes genetic mutations, activates oncogenic pathways, suppresses immune defenses, and reconfigures the TME, thereby facilitating cancer initiation and progression. Elucidating the mechanisms linking chronic inflammation to tumorigenesis will deepen our understanding of cancer biology and support the development of innovative anti-inflammatory and anticancer therapies, paving the way for more effective and personalized treatment strategies.

Inflammatory factors are a class of cytokines, chemical substances, or small molecules secreted by immune cells, epithelial cells, and other tissue cells during the inflammatory response (30). These factors play a critical role in regulating the immune system, promoting tissue repair, and maintaining homeostasis. However, the excessive or prolonged activation of inflammatory factors may lead to chronic inflammation, which can trigger a variety of diseases, including autoimmune diseases (31), cardiovascular diseases (32), and cancer (33).

Based on their function and chemical properties, inflammatory factors can be classified into several categories: Pro-inflammatory factors (34) enhance the inflammatory response by activating pro-inflammatory signaling pathways, resulting in tissue damage and abnormal cell proliferation. Second, anti-inflammatory factors (34) play a key role in maintaining the balance of the inflammatory response by inhibiting the production of pro-inflammatory factors and reducing tissue damage. In addition, chemokines (34) primarily function to recruit immune cells to the site of inflammation, thereby expanding the scope of the inflammatory response. The functions of inflammatory factors and their communication network are shown in Table 1 and Figure 1.

Inflammatory factors play a central role in the link between inflammation and cancer through various mechanisms. In GC, inflammatory factors contribute to tumorigenesis by activating signaling pathways, reshaping the TME, and suppressing immune surveillance, thus driving the entire process from early tumor formation to late-stage metastasis (98). A comprehensive understanding of the function and regulatory mechanisms of inflammatory factors will not only help elucidate the pathogenesis of GC but also provide novel insights into the development of targeted anti-inflammatory cancer therapies, laying a theoretical foundation for personalized treatment strategies.

Gastritis broadly refers to inflammatory or reactive injury of the gastric mucosa with diverse etiologies (e.g., H. pylori, autoimmune atrophic gastritis, bile-reflux/chemical injury, eosinophilic or lymphocytic gastritis). Clinically, it is important to distinguish reactive/chemical injury from leukocyte-predominant inflammatory gastritis and to record acute versus chronic patterns and anatomic distribution (antrum-predominant, corpus-predominant, or pangastritis), which in turn influence mechanisms and risks of progression from chronic inflammation to cancer (99, 100). GC is a significant global health issue, often resulting from a multifactorial process involving genetic, environmental, and microbial factors (101, 102).

When gastritis becomes chronic, it can lead to progressive damage of the stomach lining, starting with atrophy (thinning of the gastric mucosa), followed by metaplasia (the transformation of normal cells into abnormal ones) and dysplasia (abnormal cell growth) (99). These changes are considered precursors to GC. Persistent inflammation can also lead to the accumulation of genetic mutations, disruption of normal cell signaling pathways, and the activation of pro-inflammatory factors, all of which contribute to the development of cancer. If left untreated, this chronic inflammatory process can eventually promote the transformation of normal gastric cells into malignant cancer cells, resulting in GC.

IL-1 is a pivotal cytokine produced by various cell types, including monocytes, macrophages, and fibroblasts, primarily in two isoforms: IL-1α and IL-1β (174). We will focus primarily on IL-1β, IL-1α, and IL-1β, although the IL-1 family also includes the disease-associated cytokines IL-18, IL-33, and IL-36 (175). It serves as a central mediator in the immune and inflammatory responses, regulating immune activity (176), enhancing inflammation (177), and influencing cellular proliferation and tissue repair through the activation of multiple signaling pathways (178, 179). The involvement of IL-1 in gastritis (180), GC (115), and the TME (181) is extensive and multifaceted, playing a significant role in the pathogenesis and progression of these conditions.

IL-2 plays a key role in the TME and is an important immunomodulatory factor. IL-2 maintains the immune response mainly by promoting T-cell proliferation, activation and survival, and also has a major influence on immune tolerance and immunosuppression mechanisms (192). The most important are the high affinity IL-2Rα, IL-2Rβ and IL-2Rγ (193).

IL-4 is a key cytokine secreted by immune cells such as Th2 cells, mast cells, and eosinophils, and it plays a crucial role in regulating the TME (202). Its primary function is to drive a Th2-type immune response by promoting B cell differentiation into plasma cells, which secrete antibodies, while simultaneously suppressing Th1-type immune responses. IL-4 also has significant roles in anti-inflammatory processes (203), fostering immune tolerance (204), and facilitating immune escape mechanisms (205).

IL-6 is a multifunctional inflammatory cytokine secreted by a variety of cells including macrophages, monocytes, fibroblasts and tumor cells (223). It promotes the production of acute phase proteins and the recruitment of immune cells in acute inflammation, while in chronic inflammation it can be a trigger for tissue damage and disease progression. In cancer development and progression (224), IL-6 can promote tumor cell proliferation, anti-apoptosis and angiogenesis by activating JAK/STAT3 and other signaling pathways (225, 226). At the same time, IL-6 can inhibit anti-tumor immune responses.

IL-10 is an anti-inflammatory cytokine that is mainly secreted by regulatory T cells, B cells, monocytes, and TAMs, and plays an important role in maintaining immune homeostasis and inhibiting excessive inflammation (237).

IL-12 is a key pro-inflammatory cytokine that regulates immune responses and is secreted by antigen-presenting cells such as dendritic cells and macrophages (244). It promotes the differentiation of CD4+ T cells into Th1 cells (245). It drives the production of IFN-γ and enhances cell-mediated immunity (246). In addition, bridging innate and adaptive immunity, IL-12 activates NK cells and enhances their cytotoxic and antitumor functions (247). In the TME, IL-12 inhibits tumoral growth and supports anti-tumoral immunity. However, underscoring the need for balanced IL-12 expression, excessive IL-12 can lead to harmful inflammation and has been linked to autoimmune diseases (248).

The IL-17 class of pro-inflammatory cytokines is secreted by Th17 cells and their derivatives, including gamma delta T cells and natural killer T cells (260). These cytokines play a pivotal role in regulating inflammatory responses. The IL-17 family comprises IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, and IL-17F (260). Among them, IL-17A is regarded as the most representative and the most extensively studied member. By binding to its receptor, designated as IL-17R, IL-17 triggers the activation of multiple signaling pathways, resulting in the promotion of downstream cytokine production and leukocyte recruitment. This phenomenon manifests a dual effect on both immune response and tissue damage (261).

IL-23 is a pro-inflammatory cytokine that plays a pivotal role in the TME, primarily through the regulation of Th17 cell differentiation and function (270). Its function includes the maintenance of Th17 cell expansion through the activation of the JAK-STAT pathway, the promotion of inflammatory factor production (e.g., IL-17 and IL-22), and, consequently, the enhancement of mucosal barrier defense and pathogen clearance (271). However, uncontrolled activation of IL-23 has been associated with the pathogenesis of various autoinflammatory conditions, including psoriasis (272) and inflammatory bowel disease (248). Within the TME, IL-23 exhibits a dual role, functioning both to enhance anti-tumor immunity and to promote tumor progression through the mechanisms of chronic inflammation and immune escape (273). Consequently, IL-23 represents a significant target for the therapeutic management of inflammatory diseases and demonstrates potential value in the context of tumor immunotherapy.

TNF drives inflammation in H. pylori -induced gastritis by activating the NF-κB pathway, stimulating the release of other inflammatory cytokines (288, 290). This results in infiltration of immune cells and damage to the stomach lining. Chronic elevated TNF contributes to persistent inflammation and compromises mucosal repair, laying the foundation for GC (278).

In GC, TNF drives tumor progression through NF-κB and MAPK pathways, promotes angiogenesis, cell proliferation and metastasis, and suppresses antitumor immunity (291). Reflecting its dual function, despite its pro-tumor role, TNF also has apoptotic effects on tumor cells (278).

In the TME of a tumor, TNF-α plays a complex dual role, both as an inhibitor of tumorigenesis and, under certain conditions, as a potential promoter of tumor progression.

By activating cytotoxic T cells and NK cells, TNF-α enhances its anti-tumor effects. In addition, TNF-α induces tumor cell expression of death receptors (e.g., Fas (292) and TNFR1 (293)), which initiates apoptosis through extracellular pathways and inhibits tumor growth. On the one hand, TNF-α plays a key role in enhancing the antigen-presenting function and promoting the release of inflammatory factors, thereby providing the body with an effective anti-tumor immune environment (294).

Under conditions of chronic inflammation, TNF-α supports tumor development and proliferation through multiple mechanisms. First, TNF-α is able to promote angiogenesis and tumor invasion through the up-regulation of VEGF (295) and MMPs (296). Second, TNF-α suppresses the activity of effector T cells by recruiting immunosuppressive cells such as regulatory T cells (235) and MDSCs (297), creating an immune escape environment. In addition, TNF-α activates the M2-type polarization of TAMs (298) and secretes inhibitory factors such as IL-10 and TGF-β, further suppressing anti-tumor immune responses.

In summary, depending on its concentration, local environment and regulatory status of signaling pathways, the role of TNF-α in the TME varies. Therapeutic strategies based on TNF-α need to enhance its anti-tumor ability while at the same time avoiding its tumor-promoting effects. In recent years, new ideas for optimizing tumor immunotherapy have emerged, such as combination therapy targeting TNF-α signaling (299).

The future of TNF research is aimed at optimizing its therapeutic potential, particularly in autoimmune diseases and cancer treatment. Efforts are focused on refining TNF-targeted therapies to minimize side effects and improve outcomes. In cancer, the combination of TNF modulation with immune checkpoint inhibitors is being explored to boost anti-tumor immunity while addressing its role in chronic inflammation and immune tolerance. Understanding the dual role of TNF in disease progression is essential for the development of more effective, targeted therapies.

In gastritis caused by H. pylori, IFNs play an important role in the immune response. The inflammatory response induces the production of these cytokines, which increase local inflammation and recruit other immune cells (T cells, NK cells) through macrophage/dendritic cell activation (312). In H. pylori-induced gastritis, the expression of IFN-γ is elevated, enhancing the antimicrobial immune response. IFN-γ induces the expression of PD-L1, which contributes to limiting persistent inflammation and alleviating gastric mucosal tissue damage. However, PD-L1 binds to PD-1 on T cells, leading to T cell exhaustion and suppression of the immune response. This ultimately results in an immunosuppressive microenvironment that promotes tumor cell survival, metastasis, and therapeutic resistance (313). Recombinant forms of IFN-α have been used to treat melanoma (314), renal cell carcinoma (315), and GC (316) because of their ability to induce tumor cell apoptosis and enhance immune activation. However, chronic IFN signaling in the GC microenvironment may enhance tumor progression by promoting vascularization and tumor survival via pathways including VEGF and TGF-β (317, 318).

IFN activate immune responses by modulating the activity of immune cells and influencing the TME. Type I IFNs (IFN-α/β) activate antigen presentation, enhance NK cell and macrophage function, and stimulate the expression of ISGs to establish an antiviral state. They play an essential role in early immune responses to infections and tumors (319). Type II IFN (IFN-γ), produced mainly by T and NK cells, promotes Th1 differentiation, macrophage activation and antigen presentation, which are critical for controlling infection and tumor growth (320). However, excessive or prolonged IFN signaling can induce chronic inflammation, tissue damage and immune dysregulation (321). In the TME, prolonged IFN exposure can upregulate immune checkpoint molecules such as PD-L1, leading to immune tolerance and facilitating immune escape (322). In addition, prolonged IFN signaling may promote tumor cell survival, angiogenesis, and metastasis, complicating its therapeutic use. The balance between immune activation and suppression driven by IFNs is critical in cancer and chronic inflammatory diseases.

Improving their therapeutic applications, particularly in cancer, viral infections and autoimmune diseases, is the future of IFNs in medical research. New approaches aim to refine the use of IFNs to enhance immune responses against tumors. Combinations of IFNs and immune checkpoint inhibitors show promise in boosting anti-tumor immunity. Researchers are also investigating strategies to minimize the adverse effects of prolonged IFN signaling, which can contribute to chronic inflammation and immune tolerance. Future therapies may offer more effective and targeted solutions for a variety of immune-related diseases through a better understanding of the mechanisms of IFN signaling in the TME and autoimmune contexts.

CCL2 also known as MCP-1, is an important chemokine (353). It is a member of the C-C motif chemokine family. It promotes the chemotaxis of immune cells, in particular monocytes, macrophages and dendritic cells, by binding to its receptor CCR2.CCL2 (354) plays an important role in a wide variety of physiological and pathological processes, including inflammation, the immune response, the TME and immune escape (354).

CCL3 also known as MIP-1α, is an important chemokine belonging to the C-C motif chemokine family. CCL3 plays an important role in inflammation, immunomodulation, infectious diseases, and tumors (364).

CCL5 also known as RANTES, is an important chemokine that belongs to the C-C motif chemokine family (373). It is a chemokine secreted mainly by T cells, macrophages, dendritic cells, endothelial cells and tumor cells (374). It regulates the migration of immune cells, especially immune cells such as T cells, macrophages and eosinophils, by binding to CCR1, CCR3 and CCR5 receptors (375–377). CCL5 not only promotes the aggregation of immune cells, but also enhances cell-cell interactions, thereby strengthening the immune response. In addition, CCL5 is involved in the regulation of immune cell activation, proliferation, differentiation and cytokine secretion (378).

CXCL8 is an important chemokine belonging to the C-X-C motif chemokine family, also known as IL-8 (387). It is predominantly secreted by various cell types including neutrophils, macrophages, endothelial cells, fibroblasts, tumor cells and others (388). By binding to its receptors CXCR1 and CXCR2, CXCL8 exerts chemotactic effects on immune cells, in particular neutrophil recruitment and activation (387). Furthermore, CXCL8 plays important roles in physiological and pathological processes including inflammation, immune response and TME (387).

CXCL12 also known as stromal cell-derived factor 1α, is an important chemokine (396). It belongs to the C-X-C motif chemokine family. CXCL12 can be secreted by various cell types including fibroblasts, endothelial cells, macrophages, and tumor cells (397). CXCL12 binds to the CXCR4 and CXCR7 receptors and is involved in many physiological and pathologic processes, including immune response, cell migration and tumor metastasis (397, 398).

CXCL10, also known as IP-10 (IFN-γ-induced protein 10), is an important chemokine that belongs to the family of chemokines with a C-X-C motif (407). CXCL10 has been shown to be secreted by various cell types including macrophages, endothelial cells, fibroblasts and tumor cells (408). The expression of CXCL10 is significantly increased by the chemotaxis induced by IFN-γ and is involved in the chemotaxis of immune cells, the modulation of immune responses, and the immune surveillance of the TME (409).

CX3CL1, also known as fractalkine, is a unique chemokine. It belongs to the C-X3-C motif chemokine family (417). Unlike other chemokines, CX3CL1 can be expressed on the cell surface in either soluble or membrane-associated forms and plays important roles in the immune response, particularly in immune cell migration, inflammatory responses, tissue repair and the TME (418).

Among the various triggers of chronic gastritis, H. pylori infection represents the most well-characterized and potent inducer of gastric tumorigenesis. Persistent infection initiates and sustains mucosal inflammation through continuous activation of epithelial and immune signaling networks, ultimately transforming the gastric microenvironment into a pro-tumor niche. The cag pathogenicity island (cagPAI), a major virulence determinant, encodes the complete Cag type IV secretion system (Cag-T4SS) together with a set of structural and effector proteins that directly remodel host signaling at multiple levels (445, 446).

During intimate bacterial–epithelial contact, the Cag-T4SS assembles into transmembrane secretion and adhesion complexes, including the outer membrane core complex (OMCC) and sheath/axon-like structures (447). Structural components such as CagY, CagX, CagT, and CagM form the OMCC and determine the system’s material transport capacity, while effector proteins including CagA and the adhesion molecule CagL mediate host cell engagement and downstream signaling (448). CagL binds integrins (α5β1, αVβ6, etc.) with high affinity, activating the FAK/Src axis and receptor tyrosine kinase cascades (e.g., EGFR), leading to MAPK (ERK, JNK, p38) activation (449). This cascade induces AP-1 and NF-κB–dependent transcription of pro-inflammatory cytokines such as IL-8 and IL-6, establishing a strong chemokine gradient that recruits neutrophils and macrophages (450).

Concurrently, the Cag-T4SS delivers bacterial peptidoglycan (PGN) and CagA into host cytoplasm. Intracellular PGN is recognized by NOD1, triggering the canonical NF-κB and MAPK pathways that further amplify inflammatory gene expression (451). Once translocated, CagA undergoes phosphorylation at its EPIYA motifs by Src/Abl kinases; phosphorylated CagA aberrantly activates SHP2, leading to dysregulated growth factor signaling, enhanced proliferation, and motility (452, 453). Non-phosphorylated CagA binds the polarity regulator PAR1b, disrupting epithelial cell polarity and promoting epithelial–mesenchymal transition (EMT)-like changes (454). Additionally, CagA impairs DNA damage repair (e.g., BRCA1-dependent pathways), induces mitochondrial dysfunction and ROS accumulation, and increases genomic instability—all hallmarks of malignant transformation (455).

Chronic infection with cagPAI-positive H. pylori strains therefore promotes gastric carcinogenesis through sustained cytokine and chemokine secretion (IL-8, IL-6, TNF-α, IL-1β), which recruit and activate neutrophils and macrophages to produce reactive oxygen and nitrogen species (445). In parallel, persistent activation of IL-6/STAT3 and NF-κB signaling sustains epithelial survival and proliferation, while simultaneously inducing an immunomodulatory milieu characterized by the recruitment and polarization of MDSCs, regulatory T cells, and TAMs (456). These processes collectively establish a microenvironment with both pro-inflammatory and immunosuppressive features, fostering tumor initiation and progression.

With respect to inflammasome activation, studies suggest cell type– and strain-dependent variability. In macrophages and dendritic cells, H. pylori can “prime” NLRP3 via TLR2/NOD2 signaling, allowing pro–IL-1β synthesis and its Caspase-1–mediated maturation under specific stimuli. Conversely, other studies indicate weak or inhibitory effects on canonical NLRP3 activation, implying that H. pylori may fine-tune inflammasome responses to balance persistent inflammation and immune evasion (457).

HLA class I/II molecules form the core immunogenetic locus that regulates antigen presentation and determines the types of peptides presented to CD4+ and CD8+ T cells. This influences Th1/Th2/Th17 cell polarisation and the secretion of corresponding cytokine profiles (e.g. IFN-γ, IL-10, IL-1β and TNF-α) (458). Numerous studies have shown that the frequency of HLA-II alleles (particularly HLA-DQA1, HLA-DQB1 and HLA-DRB1) correlates with mucosal inflammation phenotypes and cytokine expression following H. pylori infection (459). In certain populations, specific HLA-II alleles have been found to correlate with either increased IL-10 expression or a heightened risk of pro-inflammatory factor production (e.g. IL-1β and TNF-α). This suggests that immunogenetic variation is a critical factor in explaining the differences observed in the intensity of the inflammatory response and disease susceptibility between individuals (460). Failing to consider HLA and antigen presentation polymorphisms restricts discussions of inflammatory responses to the ‘commonality’ level of pathogen-signalling pathways. This approach is unable to explain why different hosts exhibit markedly divergent inflammatory profiles and disease courses despite similar pathogen exposures.

In the relationship between gastritis and GC, inflammatory factors play a crucial role (461, 462). A long-term chronic inflammatory response lays the foundation for the development of GC in chronic gastritis, especially that caused by H. pylori (463). The specific mechanisms of evolution are shown in Figure 2. This figure systematically illustrates how chronic gastric mucosal inflammation, induced by H. pylori infection or other high-risk factors, drives the progression from gastritis to GC. It highlights the cascade of inflammatory mediators and signaling pathways involved, along with their positive feedback regulation mechanisms.

Inflammatory factors (464) such as cytokines like IL-1, IL-6, TNF-α, IL-17 and chemokines like CXCL8 and CCL2 play an important role in this process. By activating multiple oncogenic signaling pathways (464) (e.g., NF-κB, JAK-STAT, MAPK, etc.), they promote tumor cell proliferation, survival, immune escape, and enhance tumor invasiveness and metastasis.

A. In the initial phase, H. pylori infection or other risk factors compromise the gastric mucosal barrier, leading to immune cell infiltration (e.g., neutrophils, macrophages, T cells). These cells release large amounts of pro-inflammatory cytokines such as TNF-α, IL-1β, IL-6, and CXCL8, marking the onset of the gastritis response.

B. In the second phase, inflammatory cytokines activate multiple signaling pathways, primarily NF-κB and JAK/STAT axes, which regulate immune amplification, cell survival, angiogenesis, and epithelial proliferation. These pathways engage in positive feedback loops that sustain and amplify the chronic inflammatory state. “Other signal pathways” may include MAPK, PI3K/AKT, and TLRs, which cross-regulate each other to enhance stress and injury responses in the gastric mucosa.

C. In the third phase, inflammatory mediators further promote immune cell recruitment and activation—e.g., CCL2-mediated monocyte/macrophage infiltration—forming a tripartite cycle of immune cells, cytokines, and signaling pathways that reinforce local inflammation.

D. In the fourth phase, sustained inflammation induces genetic mutations, stem cell damage, and epigenetic reprogramming in the gastric epithelium, leading to precancerous lesions such as intestinal metaplasia, atrophic gastritis, and dysplasia.

E. In the final phase, chronic inflammation promotes tumorigenesis by enhancing immune evasion, inducing EMT, and facilitating angiogenesis and stromal remodeling, ultimately driving the development of GC.

Inflammatory cytokines such as IL-1β, TNF-α, and IL-6 synergistically amplify immune responses during the early stage of gastritis via classical signaling pathways including NF-κB, JAK/STAT3, and MAPK, promoting mucosal hyperplasia, angiogenesis, and immune cell infiltration. Meanwhile, negative feedback regulators such as IL-10, TGF-β, SOCS3]/, and A20 maintain mucosal homeostasis by inhibiting these signaling axes and restrict excessive inflammation during the precancerous phase. However, when these antagonistic mechanisms become dysregulated or are hijacked by tumor cells, pro-inflammatory and pro-tumorigenic signals remain persistently active, while anti-inflammatory factors paradoxically facilitate immune evasion and microenvironment remodeling, thereby driving gastric carcinogenesis. This network exhibits marked heterogeneity both temporally (from early inflammation to precancerous lesions to advanced tumors) and spatially (across different mucosal regions and tumor core versus invasive margin). Only by constructing a multidimensional systems model integrating factors, pathways, disease stages, and spatial context can the dual regulatory roles and dynamic balance of inflammation in gastritis-to-GC progression be comprehensively elucidated. Detailed mechanisms are shown in Tables 7 and 8.

Immune cells such as Treg cells, MDSCs and M2-type macrophages infiltrate the TME and form an immunosuppressive microenvironment as the inflammatory response continues (475). These immunosuppressive cells inhibit an effective anti-tumor immune response through the secretion of immunosuppressive cytokines, thus allowing tumor cells to escape from immune surveillance (475). The development of immune escape mechanisms, which allow tumors to continue to grow under the pressure of the immune system, is an important feature of GC progression (476).

Inflammatory factors play an important role in immune escape in GC (477). Factors such as TNF-α and IL-1 exacerbate immune escape by promoting infiltration of immunosuppressive cells, upregulating immune checkpoint molecules such as PD-L1, and promoting tumor cell survival through pathways such as NF-κB (478–480). Thus, under the watchful eye of the immune system, GC cells can continue to grow and metastasize.

Within the TME, the nervous system, immune inflammation, and tumor cells form a dynamically intertwined “third space” network. Neural signaling can regulate inflammatory responses, while inflammatory mediators, in turn, influence neuronal function. In parallel, both inflammation and neural activity jointly modulate tumor cell proliferation, migration, and invasion. Conversely, tumor cells can secrete various factors to remodel both the neural and immune landscape. These three components interact reciprocally and causally, constituting a “neuroinflammation–tumor” triangular interaction network (Figure 3A). The dysregulation of this network is a critical driving force behind tumor initiation, progression, and metastasis (372). Furthermore, the neuroimmune axis regulates immune responses through the vagus nerve and other neural pathways, maintaining immune homeostasis. This complex interplay acts as a double-edged sword in both inflammation and cancer. Inflammatory factors play a dual role in gastritis and GC, as shown in Figure 3B. Future research should focus on this crosstalk phenomenon, laying an important foundation for subsequent studies.

Within this network, the inflammatory response typically serves as the initiating event. Immune cells such as macrophages, dendritic cells, T cells, and microglia become activated within the TME and release a wide array of pro-inflammatory cytokines, including TNF-α, IL-1β, IL-6, and CXCL1. These cytokines not only directly promote tumor cell growth and metastasis but also act on local nerve endings, leading to increased neuronal excitability and neural remodeling.

Neural signaling regulates immune cells via adrenergic and cholinergic receptors. The sympathetic nervous system releases norepinephrine, which binds to β₂-adrenergic receptors on macrophages, dendritic cells, and T cells, promoting M2 polarization and suppressing Th1 responses. This modulation influences cytokine production, cell migration, and overall immune function. Conversely, the parasympathetic nervous system regulates neural architecture through acetylcholine or modulates immune cell recruitment, polarization, and function via neuropeptides. Simultaneously, aberrant neural fiber growth within tumors—referred to as neoneurogenesis—can enhance tumor malignancy by transferring miRNAs and lncRNAs to tumor cells via exosomal pathways.

Tumor cells also play an active role in this interactive network. They can secrete neurotrophic factors (e.g., NGF, BDNF), chemokines (e.g., CXCL12), and extracellular vesicles to induce neural regeneration or remodeling, thereby establishing a more complex “tumor–nerve” axis. Some tumors even acquire neuronal-like properties through transcriptional reprogramming—a phenomenon known as neuronal mimicry—which enhances their responsiveness to neural signals. In addition, tumor-derived factors can reshape the inflammatory microenvironment by promoting the recruitment of immunosuppressive cells such as regulatory T cells and MDSCs, thus enabling immune evasion (475, 476).

This triangular interaction network can ultimately form a positive feedback loop: inflammation promotes neural activation; neural signals regulate immune responses; immune activity further facilitates tumor progression; and tumor cells, in turn, reactivate both inflammatory and neural pathways. Therefore, targeting the “neuro–inflammation–tumor” interaction network has emerged as a promising therapeutic strategy in cancer treatment. Potential approaches include blocking neurotransmitter signaling, inhibiting neurotrophic factors, modulating immune cell polarization, or applying denervation techniques to suppress tumor progression.

In recent years, emerging high-throughput technologies such as single-cell RNA sequencing (481, 482) and spatial transcriptomics (483, 484) have been widely applied in the study of gastrointestinal diseases, offering unprecedented resolution in elucidating the relationship between inflammatory factors and gastric pathologies. These techniques enable the dissection of transcriptional heterogeneity among different cell types—such as epithelial cells, immune cells, and fibroblasts—within the gastric mucosa at single-cell resolution, allowing for precise identification of the sources and targets of inflammatory mediators. For example, in models of chronic gastritis and H. pylori infection, single-cell analysis has revealed that pro-inflammatory cytokines such as IL-6 is primarily secreted by activated macrophages and mucosa-associated T cells, and can further influence the proliferation and differentiation trajectories of gastric epithelial stem cells (234, 485). Moreover, spatial transcriptomics enables the visualization of inflammatory factor expression across distinct anatomical regions of the gastric mucosa, thereby shedding light on the spatial relationship between localized inflammation and tumor progression. These advances are reshaping our understanding of gastric disease pathogenesis from the perspectives of cellular ecology and microenvironmental remodeling, and offer more precise strategies for early diagnosis and therapeutic intervention.

New avenues for the treatment of GC are emerging, including immunotherapy, particularly suppression of immune checkpoints such as PD-1/PD-L1 antibodies (486, 487), and targeted therapies against inflammatory factors (477, 488). Through the reversal of immune suppression and the reactivation of anti-tumor immune responses, these therapies are expected to be more effective in the treatment of GC patients. However, the challenge remains how to effectively control pro-inflammatory and escape mechanisms to improve patient prognosis.