
==== Front
Cancer Biol Med
Cancer Biol Med
CBM
Cancer Biology & Medicine
2095-3941
Compuscript Ireland

39177125
j.issn.2095-3941.2024.0188
10.20892/j.issn.2095-3941.2024.0188
Review
The current role of dendritic cells in the progression and treatment of colorectal cancer
Zhang Yuanci 12*
Ji Songtao 12*
Miao Ge 12
Du Shuya 1
Wang Haojia 12
Yang Xiaohua 13
Li Ang 14
Lu Yuanyuan 1
Wang Xin 2
https://orcid.org/0000-0002-1817-803X
Zhao Xiaodi 1
1 State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, National Clinical Research Center for Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China
2 Department of Gastroenterology, Tangdu Hospital, Fourth Military Medical University, Xi’an 710038, China
3 Department of Experimental Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China
4 Department of Gastroenterology, the 988th Hospital of PLA Joint Logistics Support Force, Zhengzhou 450042, China
Correspondence to: Xin Wang and Xiaodi Zhao, E-mail: wangx@fmmu.edu.cn and leedyzhao@fmmu.edu.cn
*These authors contributed equally to this work.

15 9 2024
22 8 2024
21 9 769783
23 5 2024
25 7 2024
Copyright: © 2024 The Authors
2024
The Authors
https://creativecommons.org/licenses/by-nc/4.0/ This work is licensed under the Creative Commons Attribution-NonCommercial 4.0 International License.
Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related deaths worldwide. Dendritic cells (DCs) constitute a heterogeneous group of antigen-presenting cells that are important for initiating and regulating both innate and adaptive immune responses. As a crucial component of the immune system, DCs have a pivotal role in the pathogenesis and clinical treatment of CRC. DCs cross-present tumor-related antigens to activate T cells and trigger an antitumor immune response. However, the antitumor immune function of DCs is impaired and immune tolerance is promoted due to the presence of the tumor microenvironment. This review systematically elucidates the specific characteristics and functions of different DC subsets, as well as the role that DCs play in the immune response and tolerance within the CRC microenvironment. Moreover, how DCs contribute to the progression of CRC and potential therapies to enhance antitumor immunity on the basis of existing data are also discussed, which will provide new perspectives and approaches for immunotherapy in patients with CRC.

Colorectal cancer
dendritic cells
tumor progression
treatment strategies
National Natural Science Foundation of China82222058 National Natural Science Foundation of China82073197 National Natural Science Foundation of China82273142 National Natural Science Foundation of China82173256 This study was supported by grants from the National Natural Science Foundation of China (Grant Nos. 82222058, 82073197, 82273142, and 82173256).
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pmcIntroduction

Colorectal cancer (CRC) is a major global public health issue. The global incidence of CRC ranks third among all types of cancer and second with respect to cancer-related mortality1. According to 2020 statistics, there were nearly 2 million new cases of CRC, including anal cancer, and nearly 1 million CRC-related deaths, representing approximately 10% of all new cancer cases and cancer-related deaths, respectively2. The incidence of CRC also ranks second among the most prevalent malignant tumors in China and CRC is among the top 10 leading causes of mortality in all Chinese provinces, including autonomous regions and municipalities3. Although traditional treatments for CRC, including surgery, chemotherapy, and radiotherapy, have undergone continuous evolution, patient survival rates continue to be unsatisfactory1. The development of CRC involves a complex process of genomic and epigenetic alterations, the onset and progression of which are dynamic and complex multistep processes. These processes, in addition to several fundamental genetic mutations, are also influenced by sophisticated interactions between the CRC tumor microenvironment (TME) and mutated cells4. Immune cells, recognized as vital elements of the TME, have complex and diverse roles in tumor initiation and progression. Dendritic cells (DCs), which are the most potent antigen-presenting cells within the TME, activate the immune response to combat tumor formation and progression, thereby regulating tolerance and immunity. DCs have a key role in regulating the balance between CD8 T cell immunity and tumor antigen tolerance unlike other antigen-producing cells, such as macrophages and B cells5,6. It is currently thought that clinically detected cancers must escape anti-tumor immune response to continue to grow. DCs that have infiltrated the TME are the key immune cells that regulate or impair immune function7, so DCs must also have an indispensable role in CRC progression and associated immune processes8. This article offers a comprehensive review of the role of DCs in CRC and provides new insights into the treatment of CRC.

DCs: a collection of phenotypically and functionally heterogeneous cells

The CRC TME encompasses non-cancerous host cells, including fibroblasts, endothelial cells, and adaptive and innate immune cells, as well as acellular components, such as the extracellular matrix and cellular signaling molecules9,10. This complex and dynamic environment has an important role in cancer progression and is a vital factor affecting cancer treatment efficacy11,12. DCs, which are responsible for initiating adaptive immune responses, have a crucial role in triggering systemic antitumor immune reactions. DCs detect danger signals and identify, engulf, process, and present tumor antigens to naive T cells (i.e., immunogenic activation). Furthermore, DCs migrate to tumor-draining lymph nodes (TDLNs), thereby locally maintaining and shaping the immune network. Given the dual role in immune surveillance and phagocytosis, DCs are instrumental in connecting innate and adaptive immune responses13–15.

DCs were first discovered in the spleens of mice by the Canadian scientist, Ralph Steinman, in 1973. The name “dendritic cells” stems from the numerous dendritic or pseudopod-like projections on the surface of mature DCs, which serve as proficient antigen-presenting cells. Despite the limited number, DCs are widely distributed throughout tissues and organs. Moreover, DCs are a diverse population of antigen-presenting cells that can be categorized into different subpopulations depending on the origin and differentiation pathways16,17. These subpopulations include conventional dendritic cells (cDCs), plasmacytoid dendritic cells (pDCs), monocyte-derived inflammatory dendritic cells (MoDCs), and Langerhans cells (LCs). Additionally, a unique subgroup known as transitional dendritic cells (tDCs) has been characterized in mice and humans (Figure 1)18.

Figure 1 DC classification. Origin of dendritic cells (DCs) and the expression of specific surface markers on each subset of DCs. Human myeloid cells originate from hematopoietic stem cells (HSCs) and differentiate into granulocyte–macrophage DC progenitors (MDPs), common DC progenitors (CDPs), common monocyte progenitors (cMoPs), and common lymphoid progenitors (CLPs). CDPs and CMoPs differentiate into pre-conventional DCs (pre-pDCs) and monocytes, respectively, while pre-plasmacytoid DCs (pre-pDCs) are differentiated from CDPs. LCs originate from embryonic progenitors. Pre-pDCs further differentiate into cDC1s and cDC2s, while pre-pDCs and CLPs co-differentiate into plasmacytoid DCs (pDCs). Transitional DCs (tDCs) are derived from pDCs and cDC2s.

cDCs, which originate from blood monocytes, have a strong ability to detect tissue damage and capture, process, and present relevant antigens to T lymphocytes, thereby having a crucial role in regulating immune responses. These cDCs are primarily categorized into cDC1 and cDC2 subgroups (Figure 1). cDC1s specialize in processing and presenting intracellular antigens and are known for cross-presenting abilities, especially in presenting tumor-related antigens to CD8+ T cells, which influences antitumor immune responses19–22. Unlike other DC subsets, cDC1s have been confirmed to be the only antigen-presenting cells capable of transporting intact tumor antigens from tumor tissue to TDLNs for T-cell activation. A high percentage of cDC1s in the TME is generally associated with a better prognosis and favorable responses to immune checkpoint blockade (ICB) therapies. cDC1s, which secrete interleukin (IL)-12 and types I and III interferon (IFN), and express interferon regulatory factor 8 (IRF8) to promote antitumor immunity, may inhibit tumor cDC1s, which relies on IRF8 development, thereby limiting the antitumor effect23–25. cDC2s, while less proficient in cross-presentation than cDC1s, effectively present major histocompatibility complex (MHC) II-related antigens to CD4+ T cells, which promotes Th1, Th2, and Th17 polarization. These cells also express various toll-like receptors (TLRs), nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain containing, and other inflammation-related signaling molecules to sense various danger signals26. The relationship between cDCs and ICB provides a potential direction for DC-based immunotherapy. In addition to the traditional subgroups, a new cDC subgroup [mature and regulatory dendritic cells (mregDCs)] has recently been revealed by single-cell RNA sequencing. These cells are thought to originate from cDC1s and cDC2s after capturing tumor antigens. These cells are also referred to as LAMP3 DCs or DC3s. LAMP3 DCs or DC3s exhibit a mature phenotype that expresses high levels of immunomodulatory molecules, such as CCR7, Lamp3, Fascin1, PD-L1, and CD40. Moreover, LAMP3 DCs or DC3s exhibit significant heterogeneity within tumors and express co-stimulatory molecules to activate T cells and interact with B cells and natural killer (NK) cells to form tertiary lymphoid structures, thereby modulating immune responses27–30. Furthermore, mregDCs promote immune tolerance and influence tumor progression by releasing specific chemokines and cytokines, including CCL17, CCL19, CCL22, IL-10, IL-4, and IL-35, which facilitates the migration of regulatory T cells (Tregs) to the TME and inhibits the proliferation of CD8+ T cells, NK cells, and B cells31,32. Taken together, these studies suggest that targeting mregDCs may be a promising approach to improve patient outcomes or adjuvant enhancement of current cancer immunotherapies. However, there are few studies involving mregDC-based treatment.

pDCs are derived from myeloid and lymphoid lineages and travel to lymph nodes via the blood circulation (Figure 1). Immature pDCs exhibit tolerance and mature pDCs exhibit immunogenicity and tolerance at the same time, depending on the local environment in which pDCs are activated. Under steady-state conditions, pDCs exhibit low levels of MHC II and co-stimulatory molecules and express a limited array of pattern recognition receptors. Upon recognizing foreign nucleic acids, lymphoid-derived pDCs synthesize large quantities of type I interferon (IFN), enabling lymphoid-derived pDCs to present foreign antigens and trigger antiviral immune responses33. Additionally, lymphoid-derived pDCs generate proinflammatory cytokines and chemokines that are crucial for antitumor immunity, as evidenced by the correlation between tumor-infiltrating pDCs and CRC patient survival34–38. Studies have confirmed that close interactions between cDCs and pDCs synergistically enhance the efficacy of immune responses39,40.

Under inflammatory conditions, DCs derived from monocytes in the bone marrow or blood respond to various damage-associated molecular pattern molecules (DAMPs). moDCs facilitate cross-presentation and MHC II-restricted presentation, promote the differentiation of CD4+ T cells into different phenotypes, such as Th1, Th2, or Th17 cells, and exert significant antitumor effects15,41, even though the migratory ability is less robust and the immunostimulatory capacity is less potent than cDCs. moDCs also secrete substantial quantities of inflammatory factors, thus recruiting more immune cells to the site of inflammation and playing a pivotal role in local tissue inflammatory responses. Moreover, the CCR2-CCL2 chemokine signaling axis has been shown to be responsible for the recruitment of moDCs to the TME42,43.

LCs are the sole antigen-presenting cells residing in the epidermis and serve as the primary line of defense against external insults. Unlike other DC subgroups, LC precursors originate from embryonic hematopoietic progenitors and exhibit typical DC functions and considerable T-cell activation potential (Figure 1)44. LCs are characterized phenotypically by low levels of MHC II, moderate levels of CD11c, and high levels of C-type lectin (CD207). LC development is independent of FLT3L but requires maintenance by macrophage colony-stimulating factor (M-CSF) and transforming growth factor-beta (TGF-β). LCs have a vital role in maintaining skin homeostasis by inducing immune tolerance under physiologic conditions and initiating adaptive immune responses during infections. Human LC-derived IL-15 also promotes the proliferation of cytotoxic CD8+ T cells. Under steady-state conditions, LCs are maintained through local self-renewal45–47, yet the role in cancer has not been established.

tDCs, which are within the phenotypic continuum between pDCs and cDC2s, represent a newly discovered subgroup with origins and relationships with other DC subgroups (Figure 1). tDCs have a gene expression profile like cDCs and pDCs and are able to capture antigens, respond to stimuli, and activate antigen-specific T cells. Furthermore, tDCs have the potential to differentiate into cDC2s during viral infections with a unique proinflammatory function. tDCs are a unique cell lineage with key complementary functions during viral infections. However, owing to the absence of tDC depletion models, the functions of tDCs have not been evaluated in vivo and tDCs have not been detected in CRC18,48,49.

DCs are crucial for CRC progression

DCs exert a critical and dual impact on the progression of CRC by serving as facilitators of potent T-cell activation to elicit antitumor immune responses while also inhibiting tumor-related factors that promote CRC immune tolerance and cancer progression49. This section will detail the specific mechanisms by which DCs influence tumor progression in CRC.

DCs induce specific immune responses

Upon detection of CRC tumor antigens, DCs undergo rapid activation to present these antigens on MHC molecules. DCs recognize damage signals in the TME through pattern recognition receptors and other mechanisms, as occurs in other malignancies50,51. This activation leads to heightened expression of MHC class I and II antigens, the release of effector cytokines, such as proinflammatory cytokines [IL-12, tumor necrosis factor-alpha (TNF-α), and IL-17] and co-stimulatory molecules, and migration of DCs to TDLNs. As a result, this process induces adaptive CD8+ and CD4+ T-cell responses against tumors52. Mature DCs in the TME follow chemokine gradients toward TDLNs, thereby initiating activation of naive T cells and attracting various immune cells (Figure 2). DCs also promote B-cell proliferation and differentiation by releasing B-cell-activating factor53,54, which drives effective antitumor cytotoxic T-cell immune responses and modulates local antitumor cytotoxic T-cell function to inhibit tumor growth55. Furthermore, DCs stimulate NK cells, thereby enhancing the immune response. The release of chemokines by DCs draws new DC precursors and stimulates NK cells, which in turn recruit naive T cells to the tumor and elicits a protective CD8+ T-cell response. Activated NK cells secrete cytokines that promote DCs maturation, further amplifying T-cell-mediated antitumor immunity56. Current research indicates that an increase in activated and mature DCs infiltration in CRC could be linked to enhanced overall survival and disease-free survival rates given that CRC patients with higher DC counts have increased 5-year overall survival rates. This finding is possibly attributed to DCs secretion of IFN-γ, which activates cytotoxic T cells57.

Figure 2 Summary of the mechanisms by which DCs influence CRC progression. I. Antitumor mechanisms: When the body finds the presence of CRC tumor antigens, DCs are rapidly activated, present CRC antigens to MHC molecules, and sense damage signals in the TME through special receptors, such as pattern recognition receptors, to induce antitumor adaptive CD8+ and CD4+ T-cell responses. Mature DCs are translocated from the TME to the TDLN along a chemokine gradient, priming naive T cells and attracting T cells and other immune cells. II. Tumor-promoting mechanisms: a. After DC differentiation is blocked, an obvious immunosuppressive cytokine spectrum is formed that inhibits the activation and proliferation of T cells and weakens the immune attack on colorectal cancer cells to induce immune tolerance; b. Impaired DC differentiation promotes the accumulation of other cell subsets with immunosuppressive functions, such as MDSCs, inducing the development of Tregs, hindering DC maturation, and promoting tumor progression; c. Immunosuppressive regulation of DCs induces proliferation of Treg lymphocytes and autoreactive T cells, thereby promoting immune tolerance.

Complex relationship between DCs and tumor angiogenesis

A sophisticated interplay exists between tumor-related angiogenesis and DCs infiltration. Angiogenesis supplies tumors with essential and sufficient oxygen and nutrients, which facilitates tumor progression58. However, angiogenesis can also increase infiltration of immune cells into tumor tissues. Elevated DCs infiltration bolsters antitumor immunity through antigen exposure59.

In some instances, DCs may incite endothelial cell proliferation, migration, and tubule formation, which contributes to remodeling of the vascular endothelium and indirectly facilitates CRC proliferation. Moreover, DCs extracted from CRC patients exhibit high expression of CXCL1, which is known to enhance angiogenesis, cancer stemness, and epithelial–mesenchymal transition, and thereby promotes tumor cell migration60.

Moreover, research has shown that CRC patients infected with human papillomavirus (HPV) display reduced levels of isthmin 2 (ISM2). Low ISM2 expression is associated with increased tumor angiogenesis, resulting in CRC immune cell infiltration enhancement and a more robust immune response61–63. Low ISM2 expression combined with the antiviral response contributes to a more favorable prognosis for HPV-infected patients with CRC64. Additionally, DCs indirectly control the tumor blood supply and inhibit tumor development by releasing anti-angiogenic substances and inhibiting DCs maturation.

It is important to recognize that among patients with different types of CRC, DCs and tumor angiogenesis are intertwined and function together. Future research endeavors should further explore the specific functions and regulatory role of DCs in the initiation and progression of different types of CRC to provide novel strategies and insight for immunotherapy.

Previous investigations have revealed that complex and contradictory molecular and cellular factors in the TME significantly change the phenotype of DCs. Moreover, CRC cells can evade the local tumor-specific immune response induced by DCs, ultimately resulting in immune dysfunction within the TME.

Impaired differentiation of DCs promotes tumor progression

Compromised DC precursor differentiation programs may lead to the accumulation of other cell subpopulations with immunosuppressive functions, such as myeloid-derived suppressor cells (MDSCs), which are vital immune regulators that facilitate direct tolerance of antitumor T lymphocytes and the development of Tregs. This process inhibits the maturation of DCs, thereby aiding in tumor progression (Figure 2)65,66.

Recent investigations have shown that the differentiation and maturation of DCs from CD14+ monocyte precursors are compromised in patients with CRC, which manifests as the accumulation of an immature phenotype with low levels of NF-κB, MHC class II, and co-stimulatory molecule expression. Consequently, these immature DCs are unable to provide adequate co-stimulation and cytokine signals to T cells, hindering the proliferation of tumor-specific CD4+ and CD8+ T cells and weakening the immune response. The production of immunosuppressive cytokines, such as IL-10 and TGF-β is increased, while the levels of immunostimulatory cytokines, such as IL-12 and TNF-α, are decreased, resulting in a pronounced immunosuppressive cytokine profile that hampers T-cell activation and proliferation, diminishes immune attack against CRC, and promotes immune tolerance67–73. Among the tumor-derived cytokines that impede DCs maturation, IL-10 permanently inhibits the differentiation of monocytes into DCs and hinders the directed differentiation into the macrophage lineage (Figure 2). Conversely, IL-6 and M-CSF hinder the differentiation of CD34+ progenitor cells into DCs but fail to induce allogeneic T-cell proliferation. Elevated levels of tumor-derived vascular endothelial growth factor (VEGF) have also been correlated with an increased number of circulating immature DCs displaying an inhibitory phenotype in CRC patients66.

Tumors can also secrete other factors that impede DCs differentiation, including gangliosides, prostaglandins, and polyamines. These factors facilitate the recruitment and accumulation of immature DCs. Studies have also revealed that COX-2 is prominently expressed in CRC and via the COX-2 downstream signaling molecules [prostaglandin E2 (PGE2) and PGE2 receptors (EP2/EP4)] which suppresses DCs differentiation and maturation, dampening host antitumor immunity74. Together, these tumor factors impede DCs differentiation, interfere with the development and maturation of DCs, limit the initiation of antitumor immune responses, and strongly facilitate the evasion of tumors from the immune system in CRC patients.

Impaired antigen presentation function of DCs promotes tumor progression

The antigen-presenting function of DCs becomes compromised in patients with CRC owing to the influence of the TME, resulting in a diminished capacity for antigen uptake, processing, and presentation. This impairment negatively impacts the generation of antitumor immune responses. Dysfunction in DC cross-presentation ability is primarily linked to defects in transporting peptide-MHC class I complexes to the cell surface. Furthermore, oxidized lipids within tumor tissues have the potential to hinder antigen cross-presentation and T-cell activation through interactions with the molecular chaperone, heat shock 70 kDa protein (HSP70)75. Recent studies have elucidated the detailed mechanisms underlying the deficiency in antigen-presenting capabilities, highlighting HSP70 targeting as an attractive therapeutic strategy for CRC given the stress-induced overexpression in cancer cells compared to healthy cells76. A study by Huang et al.77 revealed that circulating levels of DCs in CRC patients were reduced to approximately 60% of control levels and total resection of the colorectal tumor restored these levels to normal. The apparent decrease in circulating DC levels was correlated with enhanced infiltration of LCs into the colorectal mucosa and a notable increase in serum TGF-β1 levels77. Analysis of DC subsets indicated that the decrease in the number of circulating DCs was predominantly attributed to alterations in the number of pDCs78. A decrease in circulating DCs could influence cytokine production and antigen presentation to T cells, thereby facilitating cancer cell evasion from host immune surveillance79.

Numerous subsets of DCs can transition into a functionally suppressive state that is referred to as regulatory DCs (DCregs), although this categorization lacks the precise definition of a defined DC subset. DCregs exhibit decreased antigen presentation and effector T-cell activation abilities. However, DCregs stimulate the proliferation of Tregs and autoreactive T cells, thereby promoting immune tolerance66. Several molecules, including IL-10, TGF-β, and indoleamine 2,3 dioxygenase (IDO), are implicated in the functional regulation of DCregs. Factors derived from tumors are also able to promote the generation of immunosuppressive regulatory DCs, thus inhibiting T-cell activity via various mechanisms and promoting tumor immune evasion.

Impaired migratory capacity of DCs contributes to tumor advancement

Direct migration of DCs to tumor sites is hindered by the reduced expression of co-stimulatory signals in patients with CRC, resulting in ineffective chemotaxis that is driven by special chemokine gradients. This impediment prevents DC migration to TDLNs, enabling the tumor to evade immune surveillance and attack, and ultimately inducing immune tolerance67,68,71,80. Chemokines, such as CCL19 and CCL21, are key factors in the DC-to-lymph node migration. CCR7 is essential for DC-migrated CCL21 and CCL19 chemokine receptors. However, tumor cells within the TME produce factors, such as VEGF, that interfere with the expression and distribution of chemokines. As a result, the chemotactic gradient leading to DC migration and migration ability are impaired81. Studies have confirmed that tumor-produced TGF-β immobilize DCs, inhibiting migration from the tumor-to-TDLNs and therefore facilitating tumor metastasis. At the same time, increased hyaluronic acid (HA) in the ECM also inhibits DCs migration82.

Increased DCs apoptosis promotes tumor progression

Apoptosis is responsible for DCs loss in the TME. Studies have indicated that high mobility group box-1 protein produced by CRC contributes to the induction of DCs apoptosis, thereby impeding the generation of lymph node DCs71,83. Esche et al.84 reported that factors derived from tumors trigger DCs apoptosis and accelerate DCs turnover. Other factors, such as gangliosides, neuropeptides, NO, and other molecules, also shorten the lifespan of DCs, with tumor-secreted gangliosides identified as inducers of DCs apoptosis85. Studies have also confirmed that purified mucin-2 (MUC2) from CRC cell lines augments DCs apoptosis, which is partly mediated by the relationship between MUC2 mucins and Siglec-3 on DCs86. Given that the role of DCs in programmed cell death is crucial for regulating the duration and intensity of immune responses, substantial depletion of DCs from the TME can lead to ineffective antitumor immunity and immune evasion.

Therapeutic strategies targeting DCs for CRC treatment

Given the foregoing discussion, it is evident that enhancing the antitumor functionality of DCs or inhibiting the immunosuppressive actions of DCs can serve as tools for coordinating both short- and long-term anticancer immunity. Currently, DC-based strategies have immense yet underexploited therapeutic potential.

Preparation and use of DC vaccines

DC vaccines involving cultivation of mature DCs in vitro reintroduce antigen-stimulated mature DCs back into the body to restore the ability of DCs to present tumor-related antigens and activate T cells, thereby eliciting a host immune response against tumor antigens. That is, DC vaccines induce the production of T lymphocytes with specific killing effects to control tumors by presenting antigens and these vaccines have been applied in some CRC patients.

There are four primary types of DC vaccines that have been developed, as follows: tumor lysate-loaded DC vaccines; tumor antigen-loaded DC vaccines; mRNA-pulsed DC vaccines; and DC-tumor fusion cell vaccines87.

In the context of CRC, the primary focus has been on tumor lysate- and tumor antigen-loaded DC vaccines. Despite notable achievements with DC vaccines, the immunosuppression induced by tumors and the functional limitations of commonly used MoDC vaccines remain as obstacles to the adoption of these vaccines. To address these obstacles, numerous novel studies have been conducted. Recently, validated research has indicated that MoDCs can load multiple tumor antigens onto MHC I and II molecules, which activate CD8+ and CD4+ T cells, respectively, thereby enhancing the antitumor immune response to MoDC vaccines and overcoming tumor antigen escape88. Considering the crucial role of pDCs in immune responses, autologous tumor antigen-loaded pDC vaccines have been investigated. This subgroup of DC vaccines overcomes the functional limitations of MoDCs, thereby better initiating or enhancing anticancer immune responses39. Research has also identified DC-derived exosomes (DCexos) as inert vesicles that are resistant to tumor-induced immune suppression and capable of targeting cancer cells89.

Vaccines loaded with pDCs or carrying DCexos are promising novel DC vaccines that can effectively overcome tumor-induced immune suppression90. According to preclinical and clinical studies, most vaccine formulations relying on DCs are not directly purified from natural DCs in the blood but rather utilize DC substitutes. In contrast to DC substitutes, natural DC subsets exhibit elevated levels of MHC molecule expression and specialized functions, highlighting the need to develop next-generation vaccines91. Clinical testing of DC vaccines in conjunction with alternative strategies, including the administration of chimeric antigen receptor T cells, cytokine-induced killer cells or NK cells, as well as recombinant cytokines or immunostimulants, holds promise for future therapeutic advances (Table 1)102.

Table 1 Therapeutic strategies for targeting DCs in CRC treatment

Strategy	Target	Clinical phase	Type of cancer	Description of treatment	Refs	
DC vaccines	CTLA-4	Preclinical study	CRC	CTLA-4 knockdown in CRC cell lysate-loaded MoDCs	79	
PD-L1/PD1	Preliminary clinical trials	Melanoma	Vaccination with autologous tumor antigen-loaded pDCs	36	
Tumor antigen	Two phase I and one phase II clinical trials	Melanoma, NSCLC, HCC	DCexo vaccines	80	
CTLA4, PD1 and PD-L1	Preclinical study	Solid tumor	Natural DC subpopulation vaccine	82	
Novel DC-related therapies	Treg	Phase II clinical trials	CRC, breast cancer, prostate cancer	TLR ligands, talimogene laherparepvec, BCG vaccine, nanoparticles	84,86–88	
DC	Preclinical study	–	Gemcitabine	92	
Preclinical study	Melanoma	Lipid nanoparticles	91	
Preclinical study	CRC	Vancomycin combined with chemotherapy drugs	93	
Clinical trials	CRC	Sitagliptin	94	
CTLA4, PD1 and PD-L1	Preclinical study	CRC	Combination of traditional ICB therapy	27	
PD-L1	Preclinical study	Hot and cold tumors	Liposome nanoparticles encapsulate STING agonist	95	
Preclinical study	CRC	OxPt/BP	96	
Combination therapy with ICB	PD-L1	Preclinical study	CRC	FLt3L & ICB	97,98	
Preclinical study	Cervical cancer, melanoma, breast cancer	PD-1 × CLEC9A bsAb & ICB	99	
Preclinical study	CRC	PTT & ICB	54	
Preclinical study	CRC	Cu2O@Au & ICB	100	
Preclinical study	CRC	OA@CuMnCs & ICB	101	
DC	Preclinical study	CRC	Bifidobacterium ICB	93	
MDSC	Preclinical study	CRC	Oleuropein & ICB	27	

Novel DC-related therapies

At present, increasing attention has been paid to the use of various DC-related adjuvants and new drugs. Studies have confirmed that the interaction between DCs and Tregs enhance immunosuppression, which is the main obstacle to immunotherapy. Targeting these suppressor cell groups, such as Tregs, is a promising strategy for chemical and immunologic interventions. Researchers have shown that the use of specific adjuvants, such as TLR ligands or cytokines, fully activates DCs while impeding the expansion and recruitment of Tregs. TLR ligands act as adjuvants with the potential to increase immune potency against a given antigen. For example, CRC cells treated with chemotherapeutic drugs, such as oxaliplatin and/or 5-fluorouracil, can induce DC activation and maturation in vaccines through TLR4, therefore enhancing the generation of antitumor T-cell immune responses in laboratory settings and in living organisms92. Gao et al.93 reported that combining DC vaccines with NK cells produced ex vivo through the release of cytokines, such as IL-2, IL-1b, and IFN-g, enhance disease-free survival in patients with CRC.

Other adjuvants, such as the oncolytic herpes simplex virus (type 1 talimogene laherparepvec) expressing GM-CSF94, the TLR7 agonist imiquimod103, and the tuberculosis Bacillus Calmette–Guérin (BCG) vaccine95, can assist DC vaccines by enhancing DC immunogenic activity, thereby inducing antitumor immune responses. Evidence from animal studies indicated that specific immune responses triggered by DCs can be enhanced by directly administering tumor antigens. Apart from adjuvant utilization, novel materials can also be used to directly deliver tumor antigens to DCs and induce tumor-specific immune responses. This approach includes strategies, such as antigen conjugation to DC-targeting antibodies and the selective targeting of DCs using nanoparticles96,97. For example, lipid nanoparticles containing DNA-encoding tumor antigens have been functionalized with mannose mimics to enhance uptake by mannose receptor-expressing DCs98. Additionally, chemotherapeutic drugs have been shown to induce apoptosis in tumor cells by releasing numerous antigens for DCs, directly enhancing DC function, and promoting DC maturation or activation, thereby inducing strong antitumor responses99.

Recent studies have shown that the chemotherapeutic drug, gemcitabine, modulates DCs, thereby reactivating HA-specific T cells at the effector location and increasing tumor-resident DCs and cross-presenting tumor-infiltrating CD8+ T cells for full effector function100. Antibiotics can also be combined with chemotherapeutic drugs, such as vancomycin and chemotherapeutic drugs, enhancing DC cross-presentation of tumor antigens and thereby activating cytotoxic CD8+ T cells104. Increasingly, non-cancer drugs that have been shown to effectively enhance DC antitumor immunity are emerging as new options for cancer treatment. Sitagliptin, a drug effective in treating type II diabetes, has been shown to effectively promote cDC1-mediated antigen presentation while inhibiting DPP4 and prevent the degradation of chemokines and cytokines that activate DCs, thereby enhancing the activation of tumor-specific CD8+ T cells and controlling tumor progression. Sitagliptin has also been reported to reduce the risk of cancer recurrence after curative surgery in CRC patients, making sitagliptin a potential anti-cancer drug101. In the future, more drugs capable of effectively enhancing DC antitumor immunity may be used in clinical settings.

A new type of tumor immune DC checkpoint inhibitor therapy has become an important treatment in recent years. Recent advances in cancer treatment have been driven by the emergence of ICB therapies, which have significantly impacted the CRC treatment. These therapies not only affect T cells but also exert direct or indirect influences on the antitumor abilities of DCs, which lays the foundation for some ICB treatments49. While approved ICB therapies, such as programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA4), have shown success in treating mismatch repair-deficient or microsatellite instability-high CRC, most advanced CRC patients with stable microsatellites do not respond well to ICB therapy105. Studies have shown that targeting multiple immune checkpoints enhances antigen uptake and interactions with effector T-cell mregDCs, suggesting that novel ICBs that integrate various traditional ICB therapies could have greater therapeutic potential. Moreover, moDCs have shown promise in ICB therapy with moDC-derived CXCL10 enhancing CD8+ T-cell migration in a PD-1 blockade setting. The attributes of moDCs have considerable predictive significance in ICB therapy and offer potential options for enhancing treatment effectiveness30.

Recent studies have presented novel strategies, such as utilizing liposomal nanoparticles to transport STING agonists to CD103+ DCs via clec9a-binding peptides. This method has been shown to augment the efficacy of anti-PD-L1 antibodies in combating tumors in mouse models106. Additionally, a new type of nanoscale coordination polymer nanoparticle, OxPt/BP, has been created to improve immunotherapy by decreasing PD-L1 expression on cancer cells and cDCs. This nanoparticle facilitates the migration of immunologically active CTLs and diminishes immunosuppressive Tregs, leading to the successful suppression of tumor growth in mouse models without negative side effects. This development presents a promising direction for future investigations of ICB therapy (Table 1)107.

Combination therapy with DC-based ICB

Combining ICB with various treatment modalities can further enhance therapeutic effects. Amplifying the number of DCs is one of the future directions. Research has confirmed that Flt3L, a growth factor involved in the proliferation of DC progenitors, improves cancer immune surveillance in mice and enhances the response to anti-PD-L1 treatment for CRC lesions108,109. Consequently, Flt3L combined with ICB treatment significantly improves survival rates in mice and outperforms Flt3L treatment alone. This combination therapy represents a future direction for treating human CRC.

Promoting the maturation of DCs, improving the activity of DCs, and enhancing DC antigen presentation function synergistically enhances the therapeutic effect. The activity of cDC1s has a critical role in initiating and sustaining antitumor T-cell responses, often determining the effectiveness of immunotherapy with ICB. To facilitate the interaction between PD-1+ T cells and cDC1s, scientists have designed a new PD-1 × CLEC9A bispecific antibody (bsAb) in mouse models that has been proven to increase antitumor immune activity and mitigate tumor progression. Compared to monospecific anti-PD-L1 antibodies, bispecific antibodies that combine PD-L1 blockade with T-cell recruitment potential, such as CD3 × PD-L1 or LAG3 × PD-L1, exhibit superior antitumor effects110. Moreover, photothermal therapy (PTT) has recently been shown to increase systemic antitumor immunity and eliminate metastatic tumors. Recent studies have demonstrated that PTT priming prior to in vivo administration of mature DCs, followed by the application of an anti-PD-L1 antibody to disrupt the interaction between tumor PD-1 and PD-L1, enhances CTL function57. Thus, combining PTT with anti-PD-L1 treatment significantly improves CRC treatment outcomes, although corollary studies are needed regarding the optimal treatment timing. Cu2O@Au serves as an effective inducer of immunogenic cell death (ICD), which enhances tumor antigen presentation and results in optimal DC maturation and the strongest in vivo immune response. This Cu2O@Au effect triggers a robust antitumor immune response. Studies have shown that combining Cu2O@Au with PD-L1 treatment initiates an effective immune response and more effectively suppresses tumor growth111. Some gut bacteria also synergize with ICB to enhance therapeutic efficacy. For example, members of the genus Bifidobacterium can stimulate DCs to produce IL-12, thereby activating adaptive immune antitumor immunity and enhancing the response to ICB. Moreover, the inosine produced by Bifidobacteria also enhance the response to ICB treatment. Therefore, supplementing inosine may promote T-cell-induced tumor killing and increase the effectiveness of ICB treatment, although this has not been formally tested in humans104. Additionally, allogeneic NK cell products have been demonstrated to activate DCs, provoking a proinflammatory response, even under immunosuppressive conditions associated with cancer. This effect has a pivotal role in the success of T-cell-based therapies and allogeneic NK cell-based cancer immunotherapies, potentially offering a promising combination therapy to improve the clinical outcomes of ICB treatment112. Oleuropein has been identified as an effective immunomodulator capable of reprogramming immunosuppressive myeloid cells into immunostimulatory subgroups, demonstrating strong antitumor effects in colon cancer models and enhancing anti-PD-1 therapy. Therefore, oleuropein has great potential in cancer treatment. Oncolytic virus therapy (OVT) enhances the immunogenic activity of DCs or delivers tumor antigens to DCs and is recognized as an effective immune therapy for CRC treatment. Notably, a new multifunctional oncolytic adenovirus developed using bimetallic ions of copper and manganese, OA@CuMnC, can induce DC maturation, enhance NK cell activity and cytotoxicity, significantly infiltrate CD4+ and CD8+ T cells into tumors, and inhibit PD-L1 expression in tumor cells. Therefore, OA@CuMnC has strong potential for use in CRC therapy (Table 1)113.

Conclusions

This review offers insight into the functions of DC subsets, the intricate mechanisms of action in CRC, and potential therapeutic strategies. DCs are renowned for antigen-presenting abilities, yet within the CRC TME DCs have dual roles. The mechanisms of action are complex and multifaceted, involving multiple processes and factors. In this context, the heterogeneity of CRC makes it difficult to generalize therapeutic strategies targeting DCs. The TME may be significantly different among patients, which requires researchers to develop more targeted and personalized treatment regimens. Therefore, future research should focus more on how tumor cells affect and alter the specific functions of DCs in vivo, which can help us make better use of DCs and contribute to the development of new therapeutics to reverse the tumor-induced changes in DC function, thereby enhancing antitumor immune function. Clinical treatment strategies based on DCs are becoming increasingly common, but application in CRC has been limited. The limited use of DC-based treatment of CRC can be attributed to two primary reasons: an incomplete understanding of the mechanism of action within CRC; and DCs comprise a heterogeneous group of immune cells with diverse subsets interacting with tumor cells in unique ways, for which there are a limited depth of clinical strategy research. Despite the increased use of immunotherapy in the treatment of CRC, the optimal time for use, treatment alternatives, safest vaccination strategies, and most effective combination therapy, have not been established. Important topics for future research will include determine the effect of immune therapy combined with DC function. This determination may involve the design of new combination regimens to maximize the synergistic effects of immune therapy and DC function. In summary, there is a pressing need to further elucidate how to effectively harness the unique functions of DCs to orchestrate potent anti-cancer immune responses, transform the phenotype from immunosuppressive-to-immunostimulatory, and guide the design of more efficacious DC-based CRC treatment plans.

Conflict of interest statement

No potential conflicts of interest are disclosed.

Author contributions

Conceived and designed the analysis: Yuanyuan Lu, Xin Wang, and Xiaodi Zhao.

Collected the data: Yuanci Zhang and Songtao Ji.

Contributed data or analysis tools: Ge Miao, Shuya Du, and Haojia Wang.

Performed the analysis: Ang Li and Xiaohua Yang.

Wrote the paper: Yuanci Zhang and Songtao Ji.
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