Immune remodeling in inflammatory bowel disease-associated colorectal cancer: Mechanisms and immunotherapeutic implications (Review)

Introduction

Inflammatory bowel disease (IBD) is a group of disorders characterized by chronic, relapsing intestinal inflammation (1,2). During disease progression, persistent infiltration of immune cells, continuous release of pro-inflammatory cytokines, and prolonged activation of mucosal immune responses are commonly observed (3-5). Colorectal cancer (CRC) arising in the setting of long-term inflammation exhibits distinct features in terms of tumor immune microenvironment composition, immune response patterns, and regulatory mechanisms compared with sporadic CRC (6). IBD-associated CRC (IBD-CRC) develops within a chronically inflamed intestinal mucosal environment, where antitumor immune responses are often insufficient and difficult to sustain (7,8).

In sporadic CRC, immune checkpoint inhibitors (ICIs) have demonstrated clear clinical benefits in patients with specific molecular subtypes (9). However, therapeutic strategies that enhance tumor immune responses by relieving immunosuppressive signaling have shown inconsistent efficacy in patients with IBD-CRC (10,11). Clinical studies indicate substantial variability in responses to immunotherapy among patients with IBD-CRC. In some cases, treatment may exacerbate intestinal inflammatory activity, and the risk of immune-related adverse events may also increase (12,13). These observations suggest that the limited efficacy of immunotherapy in IBD-CRC is not solely attributable to treatment-related toxicity and cannot be adequately explained by alterations in a single immune pathway.

Current studies on immune abnormalities in IBD-CRC have largely focused on molecular and cellular alterations, including persistent activation of inflammatory signaling pathways, expansion of immunosuppressive cell populations, and upregulation of immune checkpoint molecules (14-16). Chronic inflammation associated with IBD not only provides a permissive background for tumor development but also continuously influences the functional state of the immune system and reshapes its regulatory mechanisms through sustained inflammatory signaling (17). Under prolonged inflammatory stress, the immune system does not simply become suppressed or inactivated. Instead, its regulatory mechanisms tend to prioritize the control of inflammation and the maintenance of tissue tolerance, conditions that are not conducive to the generation of durable and effective antitumor immune responses (18,19).

To better understand the immunological characteristics of IBD-CRC, the present review first compares the major differences between sporadic CRC and IBD-CRC in terms of immune microenvironment and inflammatory background. On this basis, the functional state of the immune system under chronic inflammatory conditions is elucidated, the molecular and cellular interactions between inflammatory signaling and immune regulation are summarized, and their roles in the development and progression of IBD-CRC are examined. Furthermore, in light of the clinical performance of immunotherapy in IBD-CRC, potential reasons for the limited therapeutic efficacy are investigated, and the potential role of natural plant-derived bioactive compounds in combination immunotherapy are explored, with the aim of providing insights for future research.

Immunological differences between sporadic CRC and IBD-CRC

Although both sporadic CRC and IBD-CRC are histologically classified as malignant colorectal tumors, they differ markedly in their underlying etiological background and immune regulatory environment. In sporadic CRC, immune abnormalities typically emerge after tumor initiation and are mainly characterized by a gradually established local immunosuppressive tumor microenvironment. This includes enhanced immune checkpoint signaling, impaired antigen presentation, and other mechanisms that enable tumor cells to evade immune surveillance (9,10).

By contrast, IBD-CRC develops in the context of long-standing chronic intestinal inflammation. In this setting, immune alterations often arise prior to tumor formation and are closely associated with mucosal barrier disruption, gut microbiota dysbiosis, and the persistent activation of inflammatory cytokine networks. Evidence suggests that these two types of CRC exhibit distinct features in terms of immune cell infiltration patterns, inflammatory signaling characteristics, and mechanisms of immune suppression (13,14). Such differences may influence both the process of tumorigenesis and the responsiveness to immunotherapy.

The key immunological differences between sporadic CRC and IBD-CRC, along with their primary sources of evidence, are summarized in Table I (9-14,20-22).

Table I Key immunological differences between sporadic CRC and IBD-CRC.

Table I

Key immunological differences between sporadic CRC and IBD-CRC.

Feature	Sporadic CRC	IBD-CRC	(Refs.)
Inflammatory background	Predominantly localized tumor-associated inflammation, which usually increases after tumor development	Long-standing chronic mucosal inflammation that precedes tumor initiation	(14)
Tumor development environment	Relatively confined tumor microenvironment	Mucosal barrier disruption and persistent inflammatory environment	(20)
Immune cell infiltration	Mainly characterized by tumor-driven immunosuppression, with gradually impaired effector T-cell function	Inflammation-driven persistent immune cell infiltration with more prominent innate immune activation	(9,10)
Immunosuppressive mechanisms	Upregulation of immune checkpoints and impaired antigen presentation	Sustained chronic inflammation, enhanced regulatory immune responses, and maintenance of checkpoint signaling	(10,11)
Microbiota and barrier factors	Generally play a secondary role	More pronounced mucosal barrier damage and microbiota dysbiosis	(21,22)
Response to immunotherapy	Certain molecular subtypes (such as MSI-H) show clear benefit from immune checkpoint inhibitors	More heterogeneous responses, with potential risk of exacerbating intestinal inflammation	(10,12,13)

[i] CRC, colorectal cancer; IBD-CRC, inflammatory bowel disease-associated colorectal cancer; MSI-H, microsatellite instability-high.

Intestinal immunity in the context of inflammatory bowel disease

IBD commonly arises in the context of persistent inflammatory stimulation and continuous immune involvement and can be viewed as a disease state that gradually develops and is maintained under such conditions. As the disease progresses, the intestinal immune system is frequently mobilized and repeatedly engaged in inflammatory responses (23). Recurrent inflammatory activity disrupts the integrity of the intestinal mucosal barrier and is accompanied by long-term alterations in the tissue microenvironment, gradually leading immune responses to adopt a relatively stable pattern distinct from that observed in healthy individuals (24,25). Under these conditions, the inflammatory state characteristic of IBD can be sustained, while the baseline conditions and initiation thresholds of various immune responses, including antitumor immunity, may also be altered.

From the perspective of innate immunity, intestinal immune components are chronically exposed to stimulatory signals derived from luminal contents and barrier disruption. When the mucosal barrier remains persistently damaged, microbe-associated molecular patterns and damage-associated molecular patterns frequently coexist, suggesting prolonged activation of pattern recognition receptor-related signaling pathways (26,27). In addition, alterations in the composition of the gut microbiota are considered an important factor linking chronic inflammation to tumorigenesis. In the context of IBD, the intestinal microbiota often exhibits reduced diversity and compositional imbalance. Certain pro-inflammatory microbial communities and their metabolites can continuously stimulate the intestinal mucosal immune system, thereby amplifying inflammatory responses and disrupting immune homeostasis (28). Microbial-derived signaling molecules can participate in immune regulation through pattern recognition receptor-associated pathways such as Toll-like receptors, thereby influencing mucosal barrier integrity and the functional state of immune cells (29). Furthermore, interventions such as probiotics and prebiotics have been suggested to modulate gut microbial composition, improve the mucosal immune environment, and reduce inflammatory burden, potentially influencing the risk of IBD-CRC to some extent (30,31).

In addition to changes in microbial composition, alterations in microbiota-derived metabolites are also considered an important mechanism linking IBD with tumor development. The gut microbiota can produce a variety of metabolites, including short-chain fatty acids (SCFAs), secondary bile acids, and tryptophan-derived metabolites. These molecules can participate in immune regulation by influencing immune cell metabolism, modulating inflammatory signaling pathways, and altering mucosal barrier function (32,33). Further research has shown that under IBD conditions, the levels of immunoregulatory metabolites such as SCFAs are often reduced, while certain pro-inflammatory metabolites may increase, thereby further amplifying inflammatory responses and disrupting mucosal immune homeostasis (34).

Compared with innate immune responses triggered by acute infection, immune reactions in the context of IBD generally exhibit a relatively lower intensity but tend to persist for a longer duration (35). Under these conditions, innate immune components, including neutrophils, macrophages, and dendritic cells, are continuously recruited into mucosal immune responses. These cells maintain heightened sensitivity to environmental stimuli and display a tendency toward rapid activation upon stimulation (36,37). Adaptive immunity is likewise situated within this altered immune environment. The persistent presence of antigenic stimulation, the influence of inflammation-related cytokines, and ongoing changes in the tissue microenvironment lead to frequent participation of T and B lymphocytes in mucosal immune responses (38-40). Consequently, the activation threshold, frequency of engagement, and functional output of adaptive immune responses may be altered to some extent (41,42). Available evidence suggests that immune activity under these conditions tends to shift toward functions associated with mucosal defense and the limitation of inflammation, whereas immune responses directed toward specific antigens may be relatively attenuated (43).

Under prolonged inflammatory pressure, intrinsic regulatory mechanisms of the immune system impose certain constraints on immune responses, while tissue injury and functional impairment may occur repeatedly (44). During the progression of IBD, the immune system gradually establishes multiple feedback regulatory relationships, forming a relatively balanced state between defensive requirements and tissue tolerance (45-47). These regulatory processes coexist with chronic inflammation and become an integral component of the overall immune functional state (48). Accordingly, the objective of immune responses often shifts from the complete elimination of stimuli toward maintaining inflammatory activity within a tolerable range while minimizing tissue damage (49).

Against the background of persistent alterations in both innate and adaptive immunity, accompanied by endogenous regulatory processes, inflammation and immune activity gradually enter a state of coexistence. Continuous inflammatory signaling intertwined with regulatory immune mechanisms may influence the actual efficiency of antitumor immune responses in terms of response intensity, resource allocation, and functional execution. To facilitate understanding of this long-term remodeling process, Fig. 1 provides a schematic overview of changes in immune signaling integration, resource allocation, and metabolic orientation of the immune system under conditions of chronic inflammation.

Figure 1 Chronic inflammation-shaped immune operational state and its impact on antitumor immunity in IBD. Under IBD conditions, persistent microbial antigens and inflammatory cytokine signals maintain the immune system in a chronically activated and inflammation-prioritized state. Continuous low-intensity inflammatory inputs progressively elevate immune response thresholds, alter immune resource allocation, and drive emergency glycolysis or unstable metabolic adaptation in immune cells. As a result, immune activity is preferentially directed toward inflammation control and tissue tolerance rather than durable antitumor immunity. Although immune cells remain engaged, this remodeled operational state limits the magnitude and persistence of antitumor responses and creates conditions permissive for IBD-CRC initiation and maintenance. IBD, inflammatory bowel disease; IBD-CRC, IBD-associated colorectal cancer.

Molecular network of inflammatory-immune crosstalk

Chronic inflammatory signaling drives immune-state remodeling

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.

Table II Key immune mediators in chronic inflammatory conditions and their systemic effects on immune regulation.

Table II

Key immune mediators in chronic inflammatory conditions and their systemic effects on immune regulation.

Factor	Primary immune effects	Impact on immune system operation	(Refs.)
IL-6	Sustains inflammatory responses and supports continuous expansion of effector T cells	Elevates baseline inflammatory signaling and reshapes immune response prioritization	(52,53)
TNF-α	Amplifies inflammatory responses and participates in tissue damage and repair	Chronically occupies immune signaling resources and maintains a high inflammatory load	(54,55)
IL-1β	Promotes inflammatory cascades and enhances immune activation	Raises basal activation levels and reduces signal discrimination capacity	(56,57)
IL-17	Sustains chronic inflammation and promotes continuous recruitment of inflammatory cells	Drives inflammation-prioritized immune response programs	(58,59)
IL-23	Maintains Th17 cell stability and amplifies inflammatory circuits	Stabilizes pro-inflammatory immune axes and reduces immune state plasticity	(60,61)
IFN-γ	Enhances immune activation and antigen presentation capacity	Maintains immune system operation in a stress-adapted state under chronic inflammation	(62,63)
IL-10	Restricts inflammatory spread and maintains tissue tolerance	Elevates regulatory signaling baseline and constrains effector response amplification	(64,65)
TGF-β	Modulates immune responses and limits inflammatory expansion	Contributes to regulatory imbalance when coexisting with persistent pro-inflammatory signals	(66,67)
GM-CSF	Promotes recruitment and functional maintenance of myeloid cells	Alters immune cell composition and shapes an inflammation-biased immune ecosystem	(68,69)
CCL2, CXCL8	Mediate sustained immune cell migration and accumulation	Maintain high immune cell density and reinforce local inflammatory environments	(70,71)

[i] In addition to the immune mediators summarized above, microbiota-derived metabolites, dietary factors, environmental exposures, and stress-related neuroendocrine signaling may also contribute to chronic immune dysregulation and immune remodeling in IBD-CRC. These factors are not individually listed because the present table focuses on representative immune mediators. IL, interleukin; TNF-α, tumor necrosis factor-α; IFN-γ, interferon-γ; TGF-β, transforming growth factor-β; GM-CSF, granulocyte-macrophage colony-stimulating factor; CCL2, C-C motif chemokine ligand 2; CXCL8, C-X-C motif chemokine ligand 8; IBD-CRC, inflammatory bowel disease-associated colorectal cancer.

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).

Chronic inflammation-induced immune cell remodeling

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).

Figure 2 Mechanisms constraining antitumor T-cell function under chronic inflammatory conditions. This schematic illustrates how chronic inflammation constrains antitumor T-cell responses despite persistent immune-cell activation. The green T cell represents a relatively activated and metabolically competent phenotype that can still receive antigen-presenting signals from dendritic cells. The weak and discontinuous signal indicates suboptimal antigen presentation and insufficient costimulatory support in the chronically inflamed microenvironment. By contrast, the blue T cell represents a metabolically restricted, functionally impaired, or exhausted-like phenotype. This state may arise from prolonged inflammatory cytokine exposure, repeated low-quality antigenic stimulation, hypoxia, nutrient competition, mitochondrial stress, metabolic byproduct accumulation, and suppressive regulatory signals. Neutrophils and macrophages sustain the inflammatory background, whereas Tregs impose additional inhibitory constraints. Together, these pressures drive a shift from metabolically competent activation toward dysfunctional or exhausted-like T-cell states, thereby reducing the magnitude and durability of antitumor immunity. Tregs, regulatory T cells; DC, dendritic cell; APC, antigen-presenting cell.

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.

Immunodynamic evolution of IBD-CRC

Under the background of long-standing chronic inflammation, the development of IBD-CRC can be understood as a process in which the immune system, remaining in a persistently dysregulated state, gradually develops abnormalities across multiple functional levels. Long-term alterations in the gut microbiota and their metabolites are also considered important factors shaping the immune microenvironment of IBD-CRC. The overall immune evolutionary process of IBD-CRC is illustrated in Fig. 3. Previous research has suggested that the increased risk of CRC may be associated with long-term imbalance within the immune microenvironment (95).

Figure 3 Immune evolutionary model of tumor initiation and maintenance in IBD-CRC. Under chronic inflammatory conditions associated with IBD, colorectal cancer development follows a stage-dependent immune evolutionary trajectory. During tumor initiation, intestinal barrier disruption and innate immune-dominated inflammation create a permissive environment for early tumor-clone survival. As inflammation persists, immune response thresholds increase, and immune resources are preferentially diverted toward inflammation control rather than antitumor surveillance. This leads to a transitional state characterized by reduced effector T-cell activity. Ultimately, expanded regulatory immune networks and sustained immune checkpoint signaling contribute to a stable immune coexistence phase, in which tumor persistence is maintained under chronic immune tolerance. IBD-CRC, inflammatory bowel disease-associated colorectal cancer; Treg, regulatory T cell; PD-L1, programmed death-ligand 1; MDSCs, myeloid-derived suppressor cells.

However, this understanding is mainly derived from two types of research systems: One based on inflammation-driven animal models of colon cancer, and the other based on molecular analyses of tissue samples from patients with IBD. Because these two research approaches differ in terms of the duration of inflammation, the composition of immune cell populations, and the complexity of the microenvironment, some uncertainty remains in the current understanding of the immune evolutionary process in IBD-CRC. From the perspective of temporal changes in immune functional states, the immune evolution of IBD-CRC can be broadly divided into two stages: The tumor initiation stage and the subsequent maintenance stage. Although these stages are mechanistically continuous, they exhibit certain differences in their immunological manifestations.

Early stages of CRC initiation

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).

Disruption of the immune barrier and antigen influx

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.

Immune evasion

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.

Alteration of immune activation thresholds

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).

Tumor maintenance phase

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.

Dysregulation of immune resources

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.

Immunosuppression and immune tolerance

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).

Immune coexistence

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.

Current status and future directions of immunotherapy in IBD-CRC

Current landscape and mechanistic limitations of immunotherapy in IBD-CRC

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).

Table III Current immunotherapeutic strategies for IBD-CRC and their mechanistic limitations.

Table III

Current immunotherapeutic strategies for IBD-CRC and their mechanistic limitations.

Therapeutic category	Mechanism of action	Major limitations	(Refs.)
PD-1/PD-L1 inhibitors	Relieve PD-1/PD-L1-mediated T-cell inhibition and enhance effector T-cell activity	Highly heterogeneous efficacy; limited ability to lower antigen recognition thresholds; potential to induce or exacerbate IBD activity; risk of irAEs, including colitis exacerbation and mucosal injury	(128-130)
CTLA-4 inhibitors	Enhance initial T-cell priming and reduce regulatory T cell-mediated suppression	High risk of inflammation-related toxicity and irAEs; potential aggravation of intestinal inflammation or systemic inflammatory flares; limited efficacy in reversing established immune tolerance	(131-133)
Dual immune checkpoint blockade	Relieve inhibitory signals at multiple levels and increase the magnitude of immune activation	Markedly increased toxicity and risk of severe irAEs; potential for colitis exacerbation, mucosal injury, and systemic inflammatory flares; limited capacity to restore durable and effective antitumor immune execution	(134-136)

[i] IBD-CRC, inflammatory bowel disease-associated colorectal cancer; PD-1, programmed cell death 1; PD-L1, programmed death-ligand 1; irAEs, immune-related adverse events; CTLA-4, cytotoxic T-lymphocyte-associated protein 4.

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.

Figure 4 Conceptual comparison between single-target immunotherapy and multi-component immune modulation in IBD-CRC. Under chronic inflammatory conditions in IBD-CRC, the immune system operates under elevated activation thresholds, persistent diversion of immune resources toward inflammation control, and a metabolically constrained microenvironment. Single-target immunotherapeutic strategies, such as PD-1/PD-L1 blockade, may partially relieve inhibitory signaling but often fail to concurrently address inflammatory burden, metabolic restriction, and reduced immune plasticity, resulting in heterogeneous therapeutic responses and increased risk of inflammation-associated toxicity. By contrast, multi-component modulation exemplified by natural compounds emphasizes low-intensity, system-level regulation of inflammatory signaling, metabolic conditions, and immune regulatory networks. Rather than directly amplifying effector responses, this approach may help alleviate inflammation-driven resource consumption and improve immune system adaptability, thereby providing a conceptual framework to support the design of safer and more sustainable combinatorial immunotherapeutic strategies. IBD-CRC, inflammatory bowel disease-associated colorectal cancer; PD-1, programmed cell death 1; PD-L1, programmed death-ligand 1.

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.

Implications of multi-component natural plant interventions for immunological research in IBD-CRC

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.

Table IV Representative natural compounds with immunomodulatory and tumor-related regulatory properties relevant to IBD-CRC.

Table IV

Representative natural compounds with immunomodulatory and tumor-related regulatory properties relevant to IBD-CRC.

Category	Natural compound	Source	Immunomodulatory/anti-inflammatory features	Antitumor-related effects	(Refs.)
Monomeric compound	Curcumin	Turmeric	Modulates inflammation-tumor related signaling pathways such as NF-κB and STAT3; influences Th17/Treg immune balance	Regulates NF-κB and STAT3 mediated inflammation-tumor signaling axes	(144-146)
Monomeric compound	Resveratrol	Grapes	Antioxidant activity; regulates mitochondrial function and immune metabolic states	Modulates tumor-related pathways including Wnt/β-catenin and AMPK signaling	(147-149)
Monomeric compound	Berberine	Coptis chinensis	Improves intestinal barrier function; modulates gut microbiota and mucosal immune responses	Regulates tumor progression-related pathways such as Wnt/β-catenin and AMPK	(150-152)
Monomeric compound	Ginsenosides	Ginseng	Influences dendritic cell function and T-cell differentiation	Regulates tumor cell survival and stress signaling pathways including PI3K-AKT and MAPK	(153-156)
Herbal formula	Danggui Buxue Decoction	Angelica sinensis and Astragalus membranaceus	Regulates immunometabolism and inflammatory responses; improves inflammation-related immune imbalance	May modulate the immune microenvironment and inflammation-tumor transition in IBD-CRC	(157,158)
Herbal extract	Huaier extract	Huaier fungus	Regulates inflammatory signaling and immune responses	Suppresses colitis-associated tumorigenesis	(159)
Herbal extract	Astragaloside IV	Astragalus membranaceus	Modulates mucosal immune responses and inflammation-related signaling pathways	May inhibit the transition from colitis to colorectal cancer	(160,161)

[i] IBD-CRC, inflammatory bowel disease-associated colorectal cancer NF-κB, nuclear factor-κB; STAT3, signal transducer and activator of transcription 3; Th17, T helper 17; Treg, regulatory T cell; AMPK, AMP-activated protein kinase; PI3K-AKT, phosphoinositide 3-kinase/protein kinase B; MAPK, mitogen-activated protein kinase.

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.

Summary and perspectives

IBD-CRC can be conceptualized as a tumor entity that emerges progressively following alterations in immune status under the sustained influence of long-standing chronic intestinal inflammation. Its immune abnormalities are not necessarily dominated by a single inhibitory pathway, nor do they invariably reflect a global loss of immune function. Rather, they more commonly manifest as a state in which immune responses remain persistently engaged but are constrained in their effector capacity. Current immunotherapeutic approaches largely exert their effects by releasing inhibitory signals or enhancing immune activation; however, within the context of IBD-CRC, the clinical benefit of such strategies is often limited and accompanied by uncertain risks of exacerbating inflammation and inducing immune-related toxicities.

Multi-component immunomodulatory strategies derived from natural plants therefore warrant consideration, with their potential value lying primarily in a lower toxicity burden and their capacity to exert gradual influences on immune states shaped by chronic inflammation. Although existing evidence is insufficient to support these approaches as standalone antitumor therapies, the insights they offer, particularly with respect to mitigating treatment-related adverse effects and improving the sustainability of immune interventions, may nevertheless inform the development of combination immunotherapeutic strategies for IBD-CRC.

Availability of data and materials

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Authors' contributions

TZ, ZR, LingW, RM, LinW, JW, XC, JP and YY contributed to the conception and design of the work and drafting of the manuscript. All authors read and approved the final manuscript. Data authentication is not applicable.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Acknowledgements

Not applicable.

Funding

This work was supported by the Liaoning University of Traditional Chinese Medicine Interdisciplinary Team Construction Project for Traditional Chinese Medicine Science and Technology Innovation (grant no. 2025-Dxkjc-06-02), and the Science and Technology Plan Joint Project of Liaoning Province (grant no. 2025JH2/101800405).

References