During the long-term course of IBD, cytokines and related inflammatory signals are not transiently elevated. Instead, they persist and repeatedly accumulate, forming the basal signaling background of the chronic inflammatory microenvironment (50). These signals can regulate immune response thresholds, signaling integration, and immune resource allocation through pathways such as nuclear factor (NF)-κB and signal transducer and acitvator of transcription (STAT)3. As a result, the immune system gradually adopts an inflammation-maintaining mode of operation (51).

Existing studies show that multiple pro-inflammatory and immunoregulatory factors remain persistently abnormal in the intestinal mucosa and peripheral circulation of patients with IBD. These include interleukin (IL)-6, tumor necrosis factor (TNF)-α, IL-1β, IL-17, IL-23, interferon (IFN)-γ, IL-10, transforming growth factor (TGF)-β, granulocyte-macrophage colony-stimulating factor (GM-CSF), C-C motif chemokine ligand 2 (CCL2), and C-X-C motif chemokine ligand 8 (CXCL8) (Table II) (52-71). These factors are important for acute defense and tissue repair. However, in chronic inflammation, their long-term coexistence may promote a stable state in which pro-inflammatory, repair-related, and regulatory signals are intertwined.

Signaling axes such as IL-6/STAT3, TNF-α/NF-κB, and IL-17/IL-23 can continuously influence immune cell differentiation, metabolic states, and effector output (72,73). This shifts the immune system toward inflammation control, mucosal repair, and tissue tolerance. Such a shift is unfavorable for antigen-specific recognition and sustained antitumor effector responses (74,75). In addition, external factors, including microbiota-derived metabolites, dietary composition, environmental exposures, and stress-related neuroendocrine signals, may also participate in immune remodeling in IBD-CRC by affecting inflammatory signaling, immunometabolism, and the mucosal microenvironment (69,70).

Current evidence is mainly derived from patient tissue analyses, serum profiling, and inflammation-associated animal models such as the azoxymethane/dextran sodium sulfate model. Although these systems differ in inflammatory duration, immune cell composition, and microenvironmental complexity, they generally support the idea that persistent inflammatory signaling continuously shapes the immune microenvironment associated with IBD-CRC (65,66).

Under persistent inflammatory stimulation, immune abnormalities in IBD are characterized less by a global reduction in immune cell numbers than by functional reprogramming and altered intercellular coordination (76,77). Impaired effector T-cell function, reduced antigen-presenting capacity, sustained activation of innate immunity, and enhanced regulatory immune networks together establish the immune imbalance that underlies IBD-CRC (Fig. 2).

Within the adaptive immune compartment, persistent inflammatory signaling reshapes T-cell differentiation and compromises the maintenance of effector function. Continuous exposure to cytokines such as IL-6 and IL-1β activates STAT3-associated transcriptional programs, promoting inflammatory T-cell phenotypes. Sustained TNF-α/NF-κB signaling further maintains an aberrantly activated immune state (78-80). In parallel, hypoxia, nutrient competition, and metabolic stress within chronically inflamed tissues drive metabolic reprogramming of T cells. Increased dependence on glycolysis, mitochondrial dysfunction, and oxidative stress collectively impair long-term proliferation and cytotoxic activity (81-83).

In addition to T cells, antigen-presenting cells and innate immune cells also undergo functional remodeling. Under chronic inflammatory conditions, dendritic cells and macrophages gradually shift from transient activation toward inflammation-associated phenotypes, accompanied by reduced antigen processing and diminished capacity to initiate effective T-cell responses (84-86). In addition, neutrophils, monocyte-macrophage lineage cells, and subsets of innate lymphoid cells remain persistently engaged in inflammatory amplification and exhibit lowered activation thresholds, fixed response patterns, and altered effector functions (87-89). Enhanced neutrophil extracellular trap formation and impaired natural killer-cell effector activity further suggest that innate immune cells remain highly active but become increasingly oriented toward sustaining inflammation rather than mediating efficient antitumor surveillance (90-92).

Chronic inflammation also promotes the establishment of regulatory immune networks. TGF-β- and IL-10-mediated signaling supports the maintenance of regulatory T cells (Tregs) and restricts sustained effector immune responses through metabolic competition, the release of immunosuppressive mediators, and remodeling of the local microenvironment (93,94). Consequently, immune abnormalities in IBD-CRC do not represent immune shutdown. Instead, they reflect a remodeled immune state that prioritizes inflammation control and tissue tolerance.

Overall, chronic inflammation drives extensive immune remodeling in IBD-CRC, resulting in a unique immune landscape characterized by persistent inflammatory signaling and continuous immune cell engagement. However, antigen recognition, metabolic support, and sustained effector responses required for effective antitumor immunity are progressively constrained. This state of sustained activation but functionally restricted immunity provides a mechanistic basis for tumor immune evasion and the suboptimal efficacy of immunotherapy.

During the early stage of tumor initiation in IBD-CRC, the intestinal immune system may not yet have entered a clearly immunosuppressive state. Instead, it often remains in a relatively active condition within an immune environment dominated by chronic inflammation (96). A more prominent feature of this stage is that persistent inflammatory pressure alters the operating conditions of immune surveillance, making it difficult for the immune system to generate high-quality and sustainable elimination responses against newly emerging abnormal epithelial clones (97).

The intestinal barrier plays a crucial role in maintaining mucosal homeostasis and may also function as a link between inflammatory immunity and tumor immune surveillance. In the pathological context of IBD, recurrent inflammatory episodes can continuously damage the intestinal epithelium. Common manifestations include downregulation of tight junction proteins, thinning of the mucus layer, and imbalance in antimicrobial peptide secretion, all of which make the intestinal barrier more prone to increased permeability (98-100). Clinical research also suggests that, in patients with ulcerative colitis, the expression levels of tight junction-related molecules in the mucosa are associated with disease activity and mucosal healing status (101).

In addition to structural disruption, inflammatory cytokines may also participate in the dynamic regulation of tight junctions through multiple signaling pathways. Persistent activation of pathways such as STAT3, STAT6, and NF-κB in epithelial cells can both sustain the inflammatory background and contribute to impaired epithelial polarity and abnormal proliferative signaling (102-104). Experimental animal research suggested that, in CRC models, epithelial barrier dysfunction often precedes the formation of tumor nodules. When tight junction-related genes or proteins are functionally impaired, the severity of colitis may increase, and tumor development is more readily observed (105).

Following increased barrier permeability, microorganisms and their metabolites can continuously cross the mucosal barrier, exposing the immune system to a sustained antigen load (106). Under such conditions, limited immune resources and effector responses are often preferentially allocated to controlling inflammation and clearing microbial stimuli. Functionally, this may compress the capacity of the immune system to recognize and expand responses against low-abundance, early tumor antigens, thereby allowing abnormal epithelial clones to acquire greater opportunities for survival and accumulation under ongoing immune pressure.

During the initiation stage of IBD-CRC, immune evasion may not primarily arise from active immunosuppressive mechanisms induced by tumor cells. Instead, it may represent a passive consequence of the long-term impact of chronic inflammation on the immune system. Under persistent inflammatory stimulation, the differentiation lineage, migratory capacity, and expression patterns of costimulatory molecules in dendritic cells and macrophages may undergo significant alterations (107,108). Consequently, even when immune cell infiltration increases, it does not necessarily translate into the generation of high-quality antitumor immune responses.

Further studies suggest that the chronic inflammatory environment may alter the functional orientation of antigen-presenting cells, making them more likely to induce transient and relatively low-intensity T-cell activation (109). While such activation may contribute to the maintenance of inflammatory responses, it may not effectively translate into robust antitumor immune activity. At the same time, immune metabolic imbalance can predispose immune cells to enter states of exhaustion or reduced responsiveness. Thus, even when infiltration levels remain elevated, the functional output of immune cells may remain primarily directed toward sustaining inflammation rather than establishing effective tumor immune clearance.

Within the long-standing pathological background of IBD, the conditions required for the immune system to respond to antigenic stimulation may gradually change, often manifesting as an increased requirement for signal strength and integration to initiate effective immune responses (110). This shift in immune response thresholds is thought to contribute to the gradual limitation of immune surveillance during the initiation stage of IBD-CRC. When antigenic signals are restricted in either intensity or presentation quality, T cells, even in the presence of persistent antigen exposure, may more readily enter activation states of limited magnitude and short duration, thereby failing to fully initiate downstream effector programs (111). This process is sometimes accompanied by epigenetic regulatory changes, suggesting that the sensitivity of immune cells to early tumor antigens may decline further.

Prolonged inflammatory stimulation may also alter the molecular expression profiles and cytokine secretion patterns of dendritic cells, making antigen presentation more likely to induce limited or transient T-cell activation. As a result, tumor-associated neoantigens may have greater difficulty triggering high-quality immune responses (112). Meanwhile, mitochondrial dysfunction and reduced efficiency of oxidative phosphorylation may compromise the capacity of immune cells to sustain the energy demands required for robust immune activation (113,114).

After escaping early immune surveillance and completing tumor initiation, IBD-CRC gradually enters a tumor maintenance stage characterized primarily by long-term persistence. Compared with the immune evolutionary trajectories commonly observed during the progression of numerous solid tumors, IBD-CRC often exhibits several distinctive immunological features during this phase (115). Notably, chronic intestinal inflammation does not necessarily diminish after tumor formation; instead, it frequently persists as a long-standing background signal.

During the tumor maintenance stage, the immune abnormalities observed in IBD-CRC suggest that the overall functional state of the immune system may have undergone deeper alterations. Persistent inflammation occupies a substantial portion of immune system activity, directing immune functions toward inflammation control, barrier repair, and maintenance of tissue homeostasis (116). Consequently, even when tumor-associated antigens remain continuously present, antitumor immune responses may be difficult to sustain, allowing tumor progression to continue.

From a metabolic perspective, this shift is often reflected in altered patterns of energy allocation within immune cells. In an inflammation-dominant state, immune cells tend to support rapid, short-term response outputs, while providing insufficient metabolic support for energy-intensive, mitochondria-dependent long-term cytotoxic effects. Although effector T cells may appear phenotypically activated, they often fail to establish the metabolic conditions and functional configuration required for sustained tumor clearance (117,118). At the same time, the antigen-presenting system frequently remains under prolonged functional burden.

During the tumor maintenance stage, immune suppression and tolerance may no longer primarily manifest as short-term regulatory responses directed against specific stimuli. Instead, they increasingly resemble a relatively stable immunological background state. In this process, regulatory T cells and immunosuppressive myeloid cell subsets, under the influence of persistent local signals, may impose long-term constraints on the intensity, duration, and functional upper limit of effector T-cell responses (107,109).

Of particular interest is the possibility that immune tolerance may gradually develop within effector T cells themselves and be maintained under certain conditions. Immune checkpoint pathways, including programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte-asssociated protein 4 (CTLA-4), can contribute to the establishment and maintenance of this tolerant state by limiting effector intensity and metabolic capacity, thereby preventing effector T cells from achieving high-level functional output (119,120). At both metabolic and epigenetic levels, this tolerant state may become increasingly stabilized. Thus, immune tolerance during the tumor maintenance stage may not simply represent a passive response to tumor presence; rather, it is more likely to develop gradually within the context of chronic inflammation and persist through the combined influence of multiple factors. As a result, antitumor immune responses remain at relatively low levels over extended periods, providing conditions that support the continued persistence of IBD-CRC (117).

Under the combined influence of immune resource redistribution and tolerance mechanisms, IBD-CRC may gradually enter a relatively stable state characterized by the long-term coexistence of inflammation and tumor growth. From a spatial perspective, inflammation-dominated regions may maintain relatively high immune activity to limit tissue damage, whereas tumor-associated areas are more likely to accumulate inhibitory signals and metabolic constraints. From a temporal perspective, immune signaling pathways, metabolic programs, and epigenetic states may gradually establish mutually reinforcing interactions, rendering this immune condition relatively stable and less responsive to short-term interventions. This functional partitioning of immune signaling and activity across space and time is often associated with phenomena such as immune cell functional exhaustion, sustained expression of immune checkpoint signals, and difficulty in enhancing antitumor responses (121,122).

The state of immune coexistence suggests that IBD-CRC may enter an abnormal yet relatively fixed condition in which the immune system prioritizes inflammation control and the maintenance of tissue tolerance, while antitumor immune responses remain constrained at relatively low levels. This also implies that interventions aimed solely at relieving inhibitory signaling may not be sufficient to disrupt the established immune background. It is also noteworthy that, during this stage, IBD-CRC-associated tumor cells and their surrounding stromal components can continuously release pro-inflammatory mediators, growth factors, and metabolic products, further reinforcing local inflammatory signaling (123-125). As a result, inflammation and tumor growth may form a long-term relationship of mutual reinforcement, although not necessarily in a balanced manner, at the level of immune regulation.

In recent years, immunotherapy, particularly ICIs, has achieved clear clinical progress in several solid tumors and has partly reshaped the treatment landscape of CRC. Previous studies have shown that ICIs can achieve relatively high response rates in tumors with deficient mismatch repair or high microsatellite instability. By contrast, among patients with IBD-CRC, only some patients achieve disease control, while a substantial proportion still show limited therapeutic benefit (126,127).

In addition, immunotherapy may be accompanied by aggravated intestinal inflammation and immune-related adverse events (irAEs). These include colitis exacerbation, mucosal injury, and systemic inflammatory reactions, which may affect the feasibility and safety of immunotherapy. The major classes of currently available ICIs, including PD-1/programmed death-ligand 1 (PD-L1) inhibitors, CTLA-4 inhibitors, and dual immune checkpoint blockade, as well as their mechanisms of action and limitations in IBD-CRC, are summarized in Table III (128-136).

Current evidence suggests that the limited efficacy of immunotherapy in IBD-CRC is not simply due to immune deficiency. It also cannot be fully explained by the dominance of a single inhibitory pathway. Instead, it may be more closely related to multi-layered immune imbalance shaped by long-term chronic inflammation. Current ICI strategies mainly exert antitumor effects by relieving inhibitory signals or enhancing immune activation. However, in IBD-CRC, the immune system may undergo persistent shifts in antigen recognition, immune response thresholds, resource allocation, metabolic support, and effector maintenance. These alterations may prevent antitumor immune responses from achieving optimal efficacy. Single-target immunotherapy primarily functions to relieve established inhibitory signaling, yet it rarely ameliorates inflammatory burden and metabolic restrictions simultaneously; this distinction is illustrated in Fig. 4.

It should also be noted that ICIs may induce or exacerbate intestinal inflammation. The risks of colitis relapse, intestinal perforation, and other severe complications may also increase. This clinical concern has limited the investigation and clinical application of ICIs in IBD-CRC to some extent (137,138). In addition to ICIs and their combination regimens, some studies have attempted to improve antitumor responses by modulating inflammation-related pathways or introducing other immunotherapeutic strategies (139,140). However, in the pathological context of IBD-CRC, these exploratory interventions often face difficulty in balancing inflammatory safety with durable antitumor immunity. Overall, the clinical application of immunotherapy in IBD-CRC remains cautious and exploratory.

In IBD-CRC, immune abnormalities are shaped by the long-term combined effects of chronic inflammation, mucosal barrier damage, gut microbiota dysbiosis, immunometabolic stress, and regulatory immune networks. Therefore, single-target interventions may not be sufficient to simultaneously ensure inflammatory safety, maintain mucosal homeostasis, and restore antitumor immunity. In this disease context, natural plant-derived agents, characterized by multi-component composition, multi-target actions, and relatively mild long-term regulation, provide a perspective distinct from conventional single-target strategies for IBD-CRC immunotherapy research (141-143). The potential regulatory features of several representative natural plant-derived agents in inflammation- and tumor-related pathways are summarized in Table IV.

Mechanistically, the potential advantage of natural plant-derived components lies primarily in their integrated regulation of the 'immune response background,' rather than direct targeting of a single terminal inhibitory pathway. Representative natural bioactive compounds, such as curcumin, resveratrol, berberine, and ginsenosides, may affect inflammation- and tumor-related pathways, including NF-κB, STAT3, AMP-activated protein kinase (AMPK), Wnt/β-catenin, phosphoinositide 3-kinase PI3K-protein kinase B (AKT), and mitogen-activated protein kinase (MAPK) (144-161). Through these pathways, they may regulate inflammatory signaling intensity, immunometabolic states, epithelial barrier function, and immune cell differentiation. These interventions are more likely to act on the long-term operating conditions of the immune system. They may reduce the persistent occupation of immune resources by chronic inflammation and improve the tissue environment required for antitumor immune responses.

The low-intensity and long-term regulatory properties of natural plant-derived interventions may also be particularly relevant to the clinical context of IBD-CRC. Patients with IBD-CRC usually have a previous or ongoing background of intestinal inflammation. Strong immune activation may increase the risk of colitis exacerbation, mucosal injury, or immune-related adverse events. Therefore, the value of natural plant-derived agents should not be simply interpreted as standalone antitumor therapy. Instead, they may be better understood as a 'background-modulating strategy' before or during combination immunotherapy. Their potential effects include reducing chronic inflammatory burden, improving immunometabolic states, stabilizing the mucosal barrier, and regulating gut microbiota and their metabolites. These effects may enhance the plasticity of the immune system and support antitumor treatment responses (162-164).

In addition, some herbal formulas or extracts may better meet the need for multi-level regulation than single compounds. For example, tonic formulas or plant extracts may simultaneously affect inflammatory signaling, immunometabolism, barrier repair, and the tumor microenvironment. Current evidence is still mainly derived from animal experiments, cell-based studies, and indirect mechanistic inference. It is therefore insufficient to support these interventions as standard therapies for IBD-CRC. Nevertheless, their potential roles in reducing inflammatory background, improving immune tolerance, and supporting immunotherapy deserve further investigation. Future studies should clarify the active material basis, dose-response relationships, safety boundaries, and optimal timing and patient selection for combining natural plant-derived interventions with immune checkpoint inhibitors or other therapeutic strategies.