Immune microenvironment and immune cell dynamics in colitis-associated colorectal cancer: Mechanisms and therapeutic implications

Abstract

Colitis-associated colorectal cancer (CAC) is a form of colorectal cancer that arises and progresses within the context of chronic inflammatory bowel disease. Studies have shown that, under the influence of inflammatory cytokines and chemokines, immune cells within the tumor microenvironment play a dual role - exerting both anti-tumor and pro-tumor effects. However, it remains unclear how these immune cells undergo dynamic phenotypic shifts driven by specific inflammatory cytokines and chemokines. It examines how they transition from an early-stage state of anti-tumor immune surveillance to a late-stage state of pro-tumor immunosuppression. This review systematically elucidates the interactions and functional transformations occurring between key immune cells and immune molecules during the progression of CAC. By dissecting these complex immunoregulatory mechanisms, we provide novel insights for enhancing the therapeutic efficacy of CAC treatment while simultaneously mitigating adverse effects. Furthermore, this study offers a novel perspective for exploring the dynamic immune mechanisms underlying CAC, as well as for developing precise early biomarkers and novel targeted therapies.

Key Words: Colitis-associated colorectal cancer; Immune microenvironment; Immune cells; Cancer promotion; Cancer suppression

Core Tip: This manuscript focuses on the dual role - both anti-tumor and pro-tumor effects - played by immune cells within the microenvironment of colitis-associated colorectal cancer. Specifically, the article elucidates how inflammatory mediators, chemokines, and immune cells collectively drive the dynamic equilibrium between anti-tumor immunity and pro-tumor inflammation. By integrating the latest research advancements in the fields of immune cells, signaling molecules, and the gut microbiota, this review highlights the key immune signaling pathways and intercellular interactions that govern the progression of colitis-associated colorectal cancer.

INTRODUCTION

Inflammatory bowel disease (IBD) is an autoimmune disease characterized by chronic relapsing inflammation of the colon, encompassing two disease phenotypes: Ulcerative colitis (UC) and Crohn’s disease[1]. UC is a chronic inflammatory disease confined to the colonic mucosa and submucosa, and long-term inflammation increases the risk of developing colitis-associated colorectal cancer (CAC). CAC is a tumor distinct from sporadic colorectal cancer, and its development follows a unique “inflammation-dysplasia-carcinogenesis” sequence, involving multiple steps from chronic inflammation and epithelial dysplasia to invasive carcinoma, accompanied by DNA damage, abnormal cytokine signaling, and immune dysregulation[2-4]. CAC typically presents as multiple, flat, and broad-based invasive lesions, making it difficult to detect in the early stages of the disease through routine endoscopy[2,5]. Epidemiological studies have shown a significantly increased risk of developing colonic adenocarcinoma 8-10 years after onset in patients with long-term extensive UC, especially those with pancolitis or high histological activity[3,4,6]. Notably, although IBD has traditionally been more prevalent in Western countries, recent changes in dietary habits and lifestyles have led to an upward trend in the incidence of CAC among Asian populations - particularly in China[7,8]. This regional shift in epidemiological characteristics also suggests that environmental factors may play a potential synergistic role in the evolution of the disease. However, most current treatments focus on relieving clinical symptoms rather than studying the pathogenesis of tumors[9,10].

Regardless of the presence of dysplasia, the tumor suppressor gene TP53 in CAC typically mutates in the early stages of mucosal inflammation, while the mutation frequency of tumor suppressor genes in colorectal adenomatous polyposis is relatively late. This contrasts sharply with the classic sporadic colorectal cancer evolutionary pathway, which starts with early adenomatous polyposis mutations activating the Wnt/β-catenin pathway and eventually progresses to late TP53 mutations. The core driving force behind this unique pathological process in CAC may lie in its complex and dynamic inflammatory microenvironment shaped by chronic inflammation. In this microenvironment, persistent immune cell infiltration[11,12], release of cytokines and chemokines[13], excessive production of reactive oxygen species (ROS)[14] and reactive nitrogen species[15], and gut microbiota dysbiosis[16] work together to induce a series of molecular events in intestinal epithelial cells, including increased genomic instability, imbalance between cell proliferation and apoptosis, and epithelial-mesenchymal transition[17-19], ultimately leading to malignant transformation. From a molecular genetic perspective, carcinogenesis of IBD-associated dysplasia is due to its genetic and epigenetic abnormalities, such as microsatellite instability (MSI), chromosomal instability, and DNA/RNA methylation[20-24]. MSI phenotype tumors are characterized by an abundance of immune cells and the expression of antigens that can activate antitumor immune responses[25,26]. Studies have shown that the infiltration of specific functional immune cell subsets in CAC is associated with improved postoperative prognosis and reduced risk of recurrence in patients with stage I, II, or III CAC[27,28]. In addition, some signaling molecules associated with the activation of inflammatory signaling pathways, such as nuclear factor-κB (NF-κB), the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, and the Hedgehog pathway, also play important roles in the molecular network mechanism of the “inflammation-cancer transformation”[29]. Previous studies have confirmed that nearly all tumors exhibit immune cell infiltration. These immune cells may play a dual role: Participating in early-stage immune surveillance while simultaneously facilitating late-stage immune evasion. However, within the unique “inflammation-dysplasia-carcinoma” evolutionary trajectory characteristic of CAC, the dynamic phenotypic transitions undergone by immune cells - such as macrophage polarization or T-cell exhaustion - as well as the specific mechanisms driving these spatiotemporal shifts, remain largely unelucidated. Consequently, this review focuses specifically on the molecular networks and mechanisms underpinning the phenotypic transitions of immune cells during the progression of CAC. By integrating the latest research findings, we aim to unravel the intricate interplay among inflammatory signaling pathways, oxidative stress responses, mechanisms of cellular carcinogenesis, and the gut microbiota, and to explore the roles these factors play in remodeling the immune microenvironment and driving immune cell phenotypic alterations. Establishing a deep and systematic understanding of these mechanisms is of critical importance for formulating effective chemoprevention strategies against chronic inflammation-driven carcinogenesis, identifying novel therapeutic targets, and optimizing biomarkers for clinical surveillance (Figure 1).

Figure 1 Overview of the pathogenesis and treatment of colitis-associated colorectal cancer. This figure illustrates how gut microbiota dysbiosis, aberrant inflammatory signaling, and immune cell reprogramming collectively drive the evolutionary sequence of “inflammation-dysplasia-carcinogenesis”, while also highlighting current targeted therapeutic strategies. AMP: Antimicrobial peptide; JAK: Janus kinase; S1P: Sphingosine-1-phosphate; APE1/Ref-1: Apurinic/apyrimidinic endonuclease 1/redox factor-1; PD-1: Programmed death receptor 1; MSI: Microsatellite instability; NK: Natural killer; NF-κB: Nuclear factor-κB; STAT: Signal transducer and activator of transcription; PI3K: Phosphatidylinositol-3-kinase; AKT: Protein kinase B; CDK1: Cyclin-dependent kinase 1.

IMMUNE REMODELING IN “INFLAMMATORY-CANCER TRANSFORMATION”

In the development of CAC, the intestinal immune system gradually shifts from its initial defensive role to a pro-cancer function. Persistent inflammation leads to damaged intestinal epithelium, altered immune cell polarization, and the formation of immune escape mechanisms. In the early stages of colitis, immune cells play a protective role by clearing pathogens and repairing colonic tissue. However, during persistent inflammation, immune cells are gradually reprogrammed by tumor-associated factors, secreting growth-promoting and immunosuppressive cytokines that promote tumorigenesis. Different types of immune cells [including T cells, B cells, macrophages, dendritic cells (DCs), neutrophils, and natural killer (NK) cells] perform different functions at different stages.

T cells play an important role in the antitumor activity of CAC. γδT cells are widely distributed in the intestinal mucosa and can rapidly respond to tissue damage and stress signals in early dysplastic colon cells, independent of major histocompatibility complex molecules, recognizing and killing dysplastic intestinal epithelial cells[24,30-33]. Studies have shown that a high proportion of invasive CD8+ T and CD4+ T cells (especially Th1 cells) is associated with a good prognosis in colorectal cancer patients[21]. CD8+ T cells can recognize and directly kill abnormal intestinal epithelial cells expressing tumor-associated antigens in early colon cancer, thereby preventing tumor formation. Th1 cells activate macrophages and other immune cells by secreting cytokines such as interferon-γ, enhancing the overall antitumor immune response. However, under persistent stimulation by antigens and inflammatory signals, tumor-infiltrating CD8+ T cells enter a state of dysfunction called “exhaustion”[34,35]. Exhausted T cells highly express inhibitory receptors [such as programmed death receptor 1 (PD-1), T-cell immunoglobulin and mucin domain-containing protein 3, lymphocyte activation gene-3], and their killing ability and cytokine secretion ability are significantly reduced, thus promoting tumor escape and growth. Long-term inflammatory infiltration in tissues leads to the remodeling of the tumor microenvironment (TME)[36]. The persistent inflammatory response promotes the production of a large number of inflammatory factors [such as tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-23], which not only directly promote the proliferation, survival and mutation of epithelial cells, but also remodel the T cell response, transforming it from a protective anti-tumor response to a destructive pro-tumor response.

IL-17-producing helper T cells (Th17 cells) are capable of inducing the production of various cytokines, including IL-17, IL-21, IL-22, and IL-23. Among these, IL-23 is responsible for maintaining the activity of Th17 cells, while IL-17A and IL-22 promote epithelial repair and antimicrobial immune responses. However, under conditions of chronic inflammation, IL-17A can promote tumor cell proliferation and angiogenesis by activating the NF-κB and STAT3 signaling pathways and upregulating the expression of Bcl-2 and cyclin D1[37-40]. IL-21 enhances the response of Th17 cells by activating the STAT3 signaling pathway and upregulating the expression of the IL-23 receptor in colorectal cancer. The subsequent upregulation of IL-23 and IL-17A expression levels by Th17 cells further promotes tumor cell proliferation and the formation of intratumoral microvessels[37]. Conversely, IL-17F - another member of the IL-17 cytokine family - plays a protective role during the initiation and progression of colon tumors. In a study by Velikova et al[41], IL-17F-deficient mice in an azoxymethane/dextran sulfate sodium-induced colorectal cancer model exhibited increased vascular endothelial growth factor production and accelerated tumor growth.

Regulatory T cells (Treg cells, CD4+CD25+FoxP3+) exert anti-inflammatory effects during the early stages of colitis[42]. The transcription factor FoxP3 is the most specific marker for Treg cells and is essential for initiating and maintaining their immunosuppressive phenotype. In the context of colitis, Treg cells adopt an “effector Treg cells” phenotype (FoxP3high CD25high CD45RO+ effector Treg cells, eTregs), which enhances their anti-inflammatory activity and is characterized by sustained high expression of FoxP3[43]. However, within the highly dynamic TME, Treg cells exhibit remarkable phenotypic plasticity, often characterized by the downregulation of FoxP3 expression. Through extensive reprogramming, these cells transform into a “memory-like” or effector-like phenotype, acquiring the capacity to secrete pro-inflammatory cytokines. Paradoxically, while this reprogrammed Treg subset actively fuels the local inflammatory environment, it simultaneously suppresses the cytolytic functions of Infiltrative NK and CD8+ T cells. Consequently, this dynamic phenotypic shift significantly facilitates tumor immune evasion and establishes profound tumor-specific immune tolerance within the host.

Within or adjacent to the TME, follicular DCs (FDCs) serve as critical stromal supporting cells within tertiary lymphoid structures (TLS). FDCs, along with specific T cell subsets such as T follicular helper cells, continuously secrete key molecular mediators, notably the chemokine C-X-C motif ligand 13 (CXCL13) and B-cell activating factor (BAFF)[44,45]. CXCL13 actively recruits peripheral B cells into the TLS, facilitating their interaction with adjacent T follicular helper cells to assemble highly organized germinal centers. Concurrently, BAFF provides potent survival and maturation signals, driving robust B cell differentiation. Activated B cells eventually differentiate into plasma cells, secreting immunoglobulin G, which can bind to tumor cell surface antigens[46] and directly eliminate tumor cells through antibody-dependent cell-mediated cytotoxicity[47]. At the same time, these antibody-antigen complexes can also be captured by antigen-presenting cells such as DCs, thereby more effectively activating cytotoxic T cells. However, under conditions of prolonged chronic inflammation, excessive pro-inflammatory cytokines (such as IL-6 and IL-17A) drive lymphoid stromal fibrosis and cause the progressive depletion of FDCs. Given that FDCs are the primary source of CXCL13 and BAFF, their loss directly precipitates the structural collapse of the TLS and triggers severe B cell dysfunction. This dysfunction is characterized by a significantly impaired capacity for antibody-dependent cell-mediated cytotoxicity and a pathological skewing toward an immunosuppressive regulatory B cell (Breg) phenotype, thereby profoundly abrogating the host’s anti-tumor humoral immune response[48].

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of immature myeloid cells, including precursor cells of DCs, macrophages, and granulocytes[49]. They can be recruited by IL-17 into the TME to recognize and suppress CD14+ and CD11b+ immune cells. In addition, in CAC cells, immunosuppressive MDSCs can promote tumorigenesis and development by releasing factors such as transforming growth factor-β (TGF-β), arginase, nitric oxide, or ROS[50-52].

Besides MDSCs, tumor-associated macrophages (TAMs) are highly plastic and play an important role in regulating the immune function of the TME[53]. Based on their phenotype and function, TAMs can be divided into two subtypes: The pro-inflammatory M1 phenotype and the anti-inflammatory/pro-repair M2 phenotype. Both M1 and M2 macrophages have been identified as CD14-low, CD16-high, and CD68-positive cells, but they can be distinguished by differential expression of their specific markers, such as nitric oxide synthase 2, CD86, human leukocyte antigen class II molecules, CD163, and CD206. M1 macrophages drive Th1 cell immune responses by secreting high levels of pro-inflammatory factors such as TNF-α, IL-1β, or IL-12, thereby inhibiting tumor growth. M2 macrophages are characterized by the production of arginase 1 and immunosuppressive cytokines such as IL-10 and TGF-β, which can promote tumor progression, metastasis, and angiogenesis[54,55]. However, the impact of TAM on the prognosis of CAC remains controversial, unlike other cancer types. Some studies have shown that a high proportion of TAM is associated with a good prognosis, but these studies only use CD68 to characterize TAM, which cannot distinguish between M1 and M2 macrophages. Certain macrophage subsets, such as macrophages expressing CD80[56], CD86[57] and CX3CR1[58], are associated with high macrophage infiltration and improved prognosis in CAC. In IBD, macrophages also exhibit a pro-inflammatory phenotype and actively participate in the progression of tissue inflammation[59,60]. As cancer emerge and progress, tumor and stromal cells secrete various polarizing mediators that drive the dynamic transition of macrophages from an M1 to an M2 phenotype. Within the TME, C-C motif chemokine ligand 2 and colony-stimulating factor 1 synergistically promote the chemotactic recruitment and early survival of macrophages. Subsequently, a potent TGF-β-mediated suppressive transcriptional network downregulates the promoters of pro-inflammatory genes (e.g., TNF-α, inducible nitric oxide synthase) while upregulating immunosuppressive and pro-angiogenic genes (e.g., IL-10, vascular endothelial growth factor). Coupled with epigenetic remodeling process of lactate-induced histone lactylation[61], these factors collectively lock macrophages into a pro-tumorigenic M2 state. By secreting angiogenic factors and immunosuppressive cytokines, these M2-type TAMs significantly promote tumor progression and metastasis[62,63]. Notably, recent studies have revealed that PD-1 is significantly upregulated on intestinal macrophages within the CAC microenvironment. The engagement of PD-1 with tumor-expressed programmed death ligand-1 (PD-L1) not only impairs the phagocytic and tumor-killing capabilities of macrophages[64-66], but also exerts profound metabolic effects. Continuous PD-1 signaling inhibits the mammalian target of rapamycin pathway and glycolysis, forcing macrophages to rely on lipid oxidation for energy. This “low-energy” lipid metabolism is a hallmark of the pro-tumorigenic M2 phenotype. Therefore, targeting PD-1 on macrophages, represents a critical anti-tumor mechanism of PD-1 blockade therapies[67]. Disrupting the PD-1/PD-L1 axis not only restores the phagocytic function of macrophages but also rapidly shifts their metabolic profile from lipid oxidation back to active glycolysis. This metabolic reprogramming triggers a moderate accumulation of intracellular ROS, which in turn activates pro-inflammatory transcription factors (such as NF-κB and STAT1), fundamentally driving the repolarization of TAMs toward M1 phenotype. Underpinned by these mechanisms, PD-1 blocking antibodies (such as nivolumab or pembrolizumab) have been approved for the treatment of mismatch repair-deficient/MSI-high metastatic colorectal cancer[68,69].

DCs typically maintain gut immune homeostasis by activating T cells through antigen presentation[70]. However, in UC or CAC environments, prolonged exposure to inflammatory factors such as IL-6 and TGF-β may lead to a tolerogenic phenotype. This is characterized by low expression levels of major histocompatibility complex-II and co-stimulatory molecules (CD80/CD86), resulting in ineffective T cell activation. Concurrently, these tolerogenic DCs specifically upregulate the expression of co-inhibitory surface markers, such as PD-L1, ILT3 (CD85k), and ILT4 (CD85d), and secrete immunosuppressive metabolic enzymes, including indoleamine 2,3-dioxygenase. This tolerant DC further promotes Treg cell differentiation and inhibits Th1 immune responses, forming an immune negative feedback loop. Clinical studies have shown a positive correlation between DC infiltration and CAC stage, suggesting its important role in tumor immune escape[28,71,72]. Simultaneously, studies have also shown that certain specific phenotypes of DCs exhibit significant anti-tumor effects through high infiltration in tumor tissues[73].

NK cells are finely regulated by a variety of activating and inhibitory receptors, participating in the recognition and clearance of tumor cells through cytotoxicity. At the same time, NK cells are also affected by a variety of molecules in the TME of CAC, with downregulation of activating receptors (such as NK receptor group 2 member D) and upregulation of inhibitory receptors [such as PD-1 and T cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif domains, T cell immunoreceptor with Ig and ITIM domains (TIGIT)], resulting in impaired cytotoxicity. TIGIT is another critical co-inhibitory immune checkpoint receptor, widely expressed on the surface of both resting and activated NK cells[74]. By binding with high affinity to ligands (such as CD155/poliovirus receptor) present on the surface of tumor cells or antigen-presenting cells, TIGIT not only competitively blocks the binding of the activating receptor DNAM-1 (CD226) to these ligands but also transmits potent inhibitory signals via its intracellular immunoreceptor tyrosine-based inhibitory motif. This process directly impairs NK cell degranulation (e.g., the release of perforin and granzymes) as well as the secretion of interferon-γ, thereby resulting in significantly compromised cytotoxicity[75]. They may play a pro-cancer role in CAC tumors and peripheral blood, helping tumors evade immune surveillance[1,25,76].

During an acute exacerbation of UC, a large number of neutrophils infiltrate the body and clear pathogens by releasing extracellular traps of neutrophils[77], various proteases and ROS, but at the same time cause serious damage to surrounding tissues. The overproduction of neutrophils can continuously activate inflammatory signals and may directly promote tumor progression.

KEY INFLAMMATORY SIGNALING PATHWAYS IN THE “INFLAMMATION-CANCER TRANSFORMATION”

In the “inflammation-carcinogenesis” axis of colorectal cancer, multiple key signaling pathways are continuously and abnormally activated, forming a complex kinase signaling network that jointly regulates cell fate. At the same time, a large number of immune cells, such as neutrophils, macrophages, and T lymphocytes, continuously infiltrate the colonic mucosa of UC, releasing a large number of cytokines (such as TNF-α, IL-6, and IL-23) and inflammatory mediators, which together constitute a pro-cancer microenvironment.

NF-κB is a core signaling hub connecting inflammation and cancer[13]. Continuous activation of NF-κB enables damaged epithelial cells to resist apoptosis, but also increases the risk of mutation accumulation and malignant transformation. In the inflammatory microenvironment, inflammatory stimuli such as TNF-α, IL-1β and lipopolysaccharide (a component of the cell wall of intestinal Gram-negative bacteria) activate the IκB kinase complex, causing NF-κB to be released from its inhibitory protease IκB and enter the nucleus to initiate the transcription of a series of downstream target genes[78]. The proteins encoded by these genes have a wide range of functions, including not only inflammatory factors such as IL-6 and cyclooxygenase-2, but also a series of anti-apoptotic proteins (such as Bcl-2 and Bcl-xL) and cell cycle regulatory proteins (such as cyclin D1). These factors provide comprehensive support for the occurrence and development of tumors.

Activation of the JAK/STAT pathway, especially the sustained activation of STAT3, is another landmark event in the development and progression of colorectal cancer[79]. In the inflammatory microenvironment of UC, the levels of inflammatory factors such as IL-6 and IL-22 secreted by macrophages and T cells are significantly increased. After these cytokines bind to their receptors, they activate JAK family kinases, which in turn phosphorylate STAT3. After phosphorylated STAT3 enters the cell nucleus, it acts as a transcription factor to regulate the expression of downstream target genes, which are involved in cell proliferation, survival and angiogenesis. Furthermore, as a key kinase driving the G2/M phase transition of the cell cycle, cyclin-dependent kinase 1 (CDK1) exhibits significantly high expression and hyperactivation in CAC[80]. Within the TME, the expression of CDK1 extends beyond its conventional regulatory role in cellular proliferation. In the cytoplasm, hyperactivated CDK1 - independent of external cytokines - directly binds to and phosphorylates JAK1, thereby persistently activating the downstream JAK/STAT3 inflammatory signaling pathway[81,82]. Concurrently, this hyperactivated CDK1 stabilizes the anti-apoptotic protein survivin within tumor cells, thereby disrupting the intrinsic apoptotic pathway. Extracellularly, CDK1 counteracts the cytotoxic functions of infiltrating immune cells by upregulating PD-L1 expression and driving STAT3-mediated immunosuppressive signaling.

In addition to the core pathways mentioned above, other kinase signaling pathways also play a role in colorectal cancer. The mitogen-activated protein kinase family (including p38, extracellular signal-regulated kinase, and c-Jun N-terminal kinase) is involved in regulating inflammatory responses and cellular stress[83], among which inflammatory factors such as p38γ and IL-6 play a pro-tumorigenic role in colorectal cancer. The phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) pathway is a classic pro-growth pathway, which is also abnormally activated in colorectal cancer. It not only inhibits apoptosis but also interacts with the Wnt/β-catenin pathway to jointly promote tumor growth. Sphingosine kinase 1 and its product sphingosine-1-phosphate are important inflammatory mediators that can maintain the continuous activation of STAT3 by forming a positive feedback loop, playing an important role in the association between inflammation and cancer.

Importantly, these inflammatory signaling pathways do not operate in isolation; rather, they form a highly integrated and dynamic crosstalk network that drives CAC progression. The PI3K/AKT and mitogen-activated protein kinase pathways frequently intersect with the NF-κB cascade by promoting the phosphorylation and degradation of IκB, thereby facilitating NF-κB nuclear translocation. Furthermore, a critical synergistic interplay exists between the NF-κB and JAK/STAT3 pathways. NF-κB and STAT3 often co-regulate a broad spectrum of oncogenic and inflammatory target genes (such as IL-6 and Bcl-2), and can even physically interact to form transcriptional complexes. This intense crosstalk amplifies the inflammatory signals and establishes a robust positive feedback loop, rendering the TME highly resistant to apoptosis and highly permissive to malignant transformation.

INTESTINAL MICROBIOTA IMBALANCE

Gut microbiota homeostasis is crucial for maintaining gut health. Ulcer patients often have gut microbiota dysbiosis, characterized by a sharp decline in microbiota diversity, a reduction in beneficial bacteria, and an overgrowth of potentially pathogenic bacteria. This dysbiosis promotes the progression of chronic inflammatory diseases through multiple pathways. Short-chain fatty acids (such as butyrate) produced by beneficial bacteria have anti-inflammatory and tumor cell proliferation-inhibiting effects, and their reduced levels weaken the protective function of the gut. Metabolites (such as secondary bile acids) produced by certain harmful bacteria have direct carcinogenic effects. Dysbiosis of the gut microbiota and its products can continuously stimulate the mucosal immune system through pattern recognition receptors (such as Toll-like receptors), exacerbating the activation of inflammatory pathways such as NF-κB, forming a vicious cycle of “dysbiosis-immune abnormality-chronic inflammation”[84]. Escherichia coli carrying pks pathogenic islands can produce colibactin[85], which can directly cause double-strand breaks in epithelial cell DNA and induce gene mutations. Fusobacterium nucleatum activates the Wnt/β-catenin signaling pathway by binding its surface adhesin FadA to E-cadherin on epithelial cells, thereby promoting tumor cell proliferation[86]. Enterotoxin-producing Bacteroides fragilis induces the production of IL-17 in epithelial cells through its secreted Bacteroides fragilis toxin, thereby driving a pro-cancer inflammatory response[87].

Antimicrobial peptides (AMPs) are produced by Paneth cells, enterocytes, immune cells in the lamina propria, and the gut microbiota. They play a crucial role in the progression of colorectal cancer as key regulators of the interaction between symbiotic microbes and host tissues[88-91]. On the one hand, these peptides possess pro-inflammatory properties that protect the host from pathogens. Impaired AMP responses increase host susceptibility to gastrointestinal infections, while dysregulation of AMP synthesis leads to a decrease in the protective effect of the intestinal barrier against bacteria and increases intestinal permeability. Restoring normal AMP expression can rebalance the gut microbiota and alleviate intestinal inflammation. On the other hand, AMPs secreted by immune cells may have pro-cancer effects. The AMP cathelicidin produced by macrophages is expressed higher in colon cancer tissues than in non-cancer tissues[92,93]. It promotes colon cancer growth by inducing phosphatase and tensin homolog phosphorylation, activating the Wnt/β-catenin signaling pathway, the PI3K/AKT signaling pathway, and glycogen synthase kinase 3β phosphorylation, thereby leading to β-catenin stabilization and nuclear translocation. Among the diverse repertoire of AMPs, defensins and regenerating islet-derived protein 3 gamma (RegIIIγ) play indispensable roles in maintaining intestinal immune homeostasis and modulating the TME. As a C-type lectin secreted predominantly by Paneth cells and intestinal epithelial cells, RegIIIγ is critical for maintaining the physical spatial segregation between the gut microbiota and the host epithelial layer[94]. The downregulation or deficiency of RegIIIγ severely compromises the integrity of the intestinal mucosal barrier, leading to persistent bacterial adhesion and pathological translocation. This microbial invasion chronically hyperactivates the Toll-like receptors/MyD88-dependent inflammatory cascade, ultimately driving the malignant “inflammation-dysplasia-carcinoma” sequence. Concurrently, defensins (including both α- and β-defensins) not only exert direct bactericidal activities to sculpt and maintain a healthy intestinal microbiome but also function as potent chemokines[95]. By engaging receptors such as CC-motif chemokine receptor-6, they orchestrate the precise recruitment of specific immune cell subsets, including DCs and T cells, into the localized TME[96].

OXIDATIVE STRESS-INDUCED GENOMIC INSTABILITY

Chronic inflammation is inevitably accompanied by an “oxidative burst”. Infiltrating immune cells, particularly neutrophils and macrophages, produce large amounts of ROS through systems such as nicotinamide adenine dinucleotide phosphate oxidase[14]. This persistent state of oxidative stress is a key upstream factor leading to DNA damage, protein and lipid peroxidation, and ultimately driving cancer development. Autophagy has the function of clearing damaged organelles and misfolded proteins and is able to sense ROS activity[97]. The role of autophagy in CAC is dual. In the early stages of inflammation, normal autophagy helps clear damaged mitochondria and reduce ROS production, thereby protecting cells and inhibiting inflammation and tumorigenesis. However, once a tumor forms, cancer cells may hijack the autophagy mechanism and use it to degrade endogenous macromolecules for energy and raw materials, thereby surviving and proliferating in the nutrient-deprived TME and resisting treatments such as chemotherapy.

ROS can directly attack DNA, leading to abnormal base modifications (such as the formation of 8-hydroxydeoxyguanosine) and single-strand or double-strand breaks[98]. 8-hydroxydeoxyguanosine is a common form of DNA damage. If it cannot be repaired in time, it is very easy to cause G:C to T:A transversion mutations during DNA replication, which is one of the important sources of gene mutations in CAC. Continuous DNA damage exceeding the cell’s repair capacity will inevitably lead to genomic instability, including point mutations, chromosomal aberrations and MSI, which are the cornerstones of tumorigenesis. Especially in CAC, since inflammation-induced p53 mutations are early events, it is more difficult for cells to initiate apoptosis when faced with DNA damage, thus creating conditions for the survival and proliferation of mutant cells.

ROS are not only damage molecules but also important signaling molecules. They sense the intracellular redox state in this complex redox network and regulate downstream DNA repair and gene transcription programs accordingly. Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) is a dual-function oxidoreductase[99,100]. On the one hand, it acts as a key endonuclease in the DNA base excision repair pathway, responsible for repairing oxidative DNA damage. On the other hand, as an oxidoreductase, it reduces various oxidized and inactivated transcription factors (such as NF-κB, STAT3, activating protein-1) to a DNA-binding active state. This dual function makes APE1/Ref-1 a key node connecting oxidative stress, DNA repair, and inflammatory signaling pathways. The balance of its activity directly affects the fate of cells in inflammatory environments. Brahma-associated gene 1 (The SMARCA4, BRG1)[101] is the core ATPase subunit of the switch/sucrose non-fermentable chromatin remodeling complex and is crucial for maintaining intestinal epithelial cell homeostasis and responding to oxidative stress. Deficiency of BRG1 leads to excessive ROS production, increasing susceptibility to dextran sulfate sodium-induced colitis and CAC. Conversely, activation of the nuclear factor E2-associated factor 2 (Nrf2)/heme oxygenase-1[102] signaling pathway can effectively alleviate oxidative stress damage in UC and CAC and exert anticancer effects.

MONITORING AND EARLY DETECTION

Due to the insidious and invasive nature of CAC, effective endoscopic monitoring is crucial for high-risk IBD patients. Current guidelines recommend colonoscopy monitoring to begin 8-10 years after UC diagnosis. High-resolution white light endoscopy combined with targeted biopsy has gradually replaced traditional randomized multi-site biopsy, while the application of chromoendoscopy and virtual chromoendoscopy has further improved the detection rate of flat or microdysplastic lesions[103]. In addition, the search for reliable non-invasive biomarkers is a current research hotspot. By detecting specific DNA methylation patterns (such as eyes absent homolog 4, bone morphogenetic protein 3), mutated genes (such as p53), or microRNAs (such as miR-31) in feces or blood[104], it is hoped that tools can be developed to assist endoscopic monitoring and more accurately stratify patients at risk.

CHEMOPREVENTION AND TREATMENT

The core of chemoprevention for CAC lies in the effective and sustained control of intestinal inflammation. 5-aminosalicylic acid is considered to have a certain chemopreventive effect as a first-line treatment for UC[105]. Immunosuppressants such as azathioprine and anti-TNF-α biologics can theoretically reduce the risk of CAC by deeply inhibiting inflammation, but relevant clinical evidence still needs to be accumulated[106]. With the elucidation of molecular mechanisms, novel targeted drugs have shown great potential. JAK inhibitors (such as tofacitinib, ruxotinib, and utpatinib) can not only effectively control UC inflammation by blocking the JAK/STAT pathway, but may also directly block key oncogenic pathways[107]. However, although first-generation non-selective inhibitors (such as tofacitinib, which targets JAK1 and JAK3) can induce clinical remission in UC through broad-spectrum immunosuppression[108], they are associated with risks of venous thromboembolism and severe infections. In contrast, second-generation highly selective inhibitors (such as upadacitinib and filgotinib, which preferentially target JAK1)[109-111] achieve superior intestinal mucosal repair by specifically blocking the IL-6/JAK1/STAT3 inflammatory axis; concurrently, they preserve JAK2-mediated hematopoietic function as well as essential immune surveillance capabilities. Modulators targeting the sphingosine-1-phosphate receptor (such as ozanimod) have also achieved success in the treatment of UC[112]. A more forward-looking strategy is to develop drugs that target redox signaling hubs, such as inhibitors that specifically regulate the redox function of APE1/Ref-1 (APX3330). As a novel oral small-molecule inhibitor specifically targeting the redox signaling function of APE1/Ref-1, it effectively modulates downstream NF-κB activation[113,114], thereby suppressing inflammatory responses and tumor progression. Dimethyl fumarate[115], an Nrf2 agonist, has previously been used for the treatment of multiple sclerosis. Studies indicate that dimethyl fumarate potently activates Nrf2 by alkylating Keap1, thereby scavenging ROS and directly inhibiting pro-inflammatory signaling within the NF-κB pathway. These drugs are expected to block the “inflammation-cancer transformation” from a more upstream link[99,116].

CONCLUSION

The transformation of colitis into colorectal cancer is a complex pathological process driven by chronic inflammation, involving multiple signaling pathways, cell types, and molecular events. In these processes, functional differences among various immune cells and gut microbiota dysbiosis collectively shape the pro-cancer microenvironment. Inflammatory signaling pathways such as NF-κB and JAK/STAT are core drivers of sustained inflammatory response activation, while oxidative stress and its regulatory networks (such as APE1/Ref-1 and Brahma-related gene 1/Nrf2) serve as crucial bridges connecting inflammatory damage and genomic instability. Current research advances have not only deepened our understanding of the unique pathogenesis of CAC but also provided new insights for clinical practice. Future research directions lie in integrating multi-omics data - specifically through the application of single-cell RNA sequencing and spatial transcriptomics technologies - to construct high-resolution spatiotemporal molecular network models. These advanced methodologies will allow us to precisely map the dynamic phenotypic switching of immune cells and their intricate spatial crosstalk within the TME. Ultimately, such approaches aim to discover more precise early diagnostic biomarkers and more effective targeted intervention strategies, achieving effective prevention and treatment of colitis-related cancers and improving the long-term prognosis of IBD patients.