Plasmacytoid dendritic cells have been shown to accumulate in the sentinel and metastatic lymph nodes in melanoma (31). Circulating pDCs from patients with melanoma have been found to express higher amounts of CCR6 and CXCR4, while their corresponding ligands CCL20 and CXCL12 are expressed on melanoma cells, suggesting that the CCR6/CCL20 and CXCR4/CXCL12 axes promote pDC migration from blood to melanoma foci (27, 34, 50, 51). Remarkably, CCL17, CCL22, and matrix metalloproteinase-2 found in the melanoma microenvironment have been shown to be associated with pDC accumulation (32). Some studies have also shown that pDCs migrating into the melanoma microenvironment are associated with early relapse and poor prognosis (26, 27, 30, 31).

Mediators of the tumor microenvironment act on tumor-infiltrating pDCs directly to suppress the production of IFN-I and mediate immunosuppression. Melanoma cells produce the immunosuppressive cytokines PGE2, IL-10, and TGF-β, which directly suppress IFN-I production by inhibiting TLR-7/9 and IRF7 expression on pDCs. Moreover, melanoma cells express Wnt5a, which inhibits TLR-mediated pDC activation and IFN-I production. Wnt5a potentiates melanoma metastasis via induction of the epithelial-to-mesenchymal transition in a protein kinase C-dependent manner (26, 27) (Figure 1A). IFN-I production may also be inhibited by ILT7, a ligand combined with BST2, which is expressed on melanoma cells. pDCs preferentially express ILT7, and the interaction between ILT7 and BST2 is involved in pDC and tumor crosstalk (52, 53).

Besides low IFN-α production, immunosuppressive mediators secreted by pDCs induce Tregs or suppress Th2 cell secretion to prevent an effective antitumoral response. pDCs in the tumor site express the immune-suppression molecules OX40L and ICOSL, which support melanoma progression (30). pDC infiltration is strongly associated with primary melanoma cell expression of activated signal transducer and activator of transcription 3, which is constitutively expressed in cancer and is thought to be a significant mediator of tumor-induced immunosuppression (31). Melanoma-associated pDCs have been shown to express high levels of IDO, suggesting that melanoma-derived signals may block pDC activation, thereby contributing to immune evasion (27, 31, 54, 55) (Figure 1B). Moreover, pDCs in the tumor microenvironment trigger IL-5/IL-13-secreting Th2 cells and IL-10-secreting Tregs through the expression of OX40L and ICOSL. These cytokines may inhibit cytotoxic T-cell functions and directly favor melanoma growth (32) (Figure 1C).

The interaction between tumor-infiltrating pDCs and other immune cells results in immunosuppression. MHC II molecules on melanoma cells bind to lymphocyte-activated gene 3 (LAG3) expressed on the surface of pDCs, resulting in their tolerogenic activation. Accordingly, LAG3⁺ pDCs display a slightly activated phenotype and produce IL-6 in vivo. IL-6 production by pDCs induces CCL2 production by monocytes. CCL2 is an essential chemokine that functions during the recruitment of myeloid-derived suppressor cells (MDSCs) to the tumor site. Hence, the recruitment of LAG3⁺ pDCs into the tumors and their activation in the absence of IFN-I production drive MDSC-mediated immune suppression (56, 57) (Figure 1D). As such, the counter-regulatory immune mechanisms in melanoma exhibit extensive signaling crosstalk. IDO is expressed by pDCs, whereas MDSCs, programmed death ligand 1 (PD-L1)⁺ T cells, and CTLA-4⁺ Tregs are strongly interconnected and associated with advanced disease and negative outcome. Thus, combination treatments targeting these markers can lead to a synergistic response (55, 58).

Various types of leukemia, multiple myeloma (MM), and malignant lymphoma are collectively defined as hematological malignancies. Among these hematological malignancies, pDCs have been reported to be mostly associated with the pathophysiology of MM, chronic lymphocytic leukemia (CLL), and chronic myelomonocytic leukemia.

Breast cancer and ovarian cancer frequently occur in women. Most patients present with metastases, leading to increased numbers of dysfunctional pDCs at both primary and metastatic sites, such as the bone or enterocyte (28). pDC infiltration in primary localized breast cancer is correlated with poor survival, suggesting that these immune cells may contribute to tumor progression and tumor metastases (35, 66).

Hepatocellular carcinoma is the most common type of liver cancer; however, the role of pDCs in HCC is not clear. Recent studies have demonstrated that the numbers of pDCs are increased in tumor tissue and decreased in blood of patients with HCC (82, 83), suggesting that peripheral pDCs migrate to liver lesions in patients with HCC. In addition, pDCs exposed to tumor-derived factors would enhance IL-10 production by CD4⁺ Tregs through upregulation of ICOSL (83). This can help tumor cells escape the immune system. In vitro, HSC-derived pDC-based vaccines are highly potent inducers of tumor-reactive T-cell and NK cell responses (84). These finding may provide insights into appropriate immunotherapies for HCC using pDCs.

To date, few studies have explored the role of pDCs in GC. Yu et al. found a positive correlation between pDCs and ICOS⁺ Tregs in peripheral blood and peritumor tissue from patients with GC (12). Additionally, Yang et al. demonstrated that CD123⁺ pDCs in tumor tissue and tumor draining lymph nodes may contribute to Treg development and promote tumor tolerance in the colorectal cancer (CRC) tolerogenic milieu (85). Briefly, pDCs play a potential role in recruiting Tregs, and both participate in the immunosuppression microenvironment of GC and CRC.

Studies of pDCs in lung cancer have mostly focused on non-small cell lung carcinoma (NSCLC). The proportion of pDCs is significantly increased in the peripheral blood and tumor tissues of patients with NSCLC (44, 45).

In NSCLC, pDCs show immunosuppressive phenotypes, as determined by higher levels of CD33 and PD-L1. Based on the characteristics of lung tumor-associated pDCs, pDCs are able to produce high levels of IL-1α in an AIM2-dependent manner, facilitating tumor cell proliferation in the lung (45). Moreover, a study of pDCs in NSCLC patients with different clinical stages demonstrated that elevated pDC numbers were observed in cases with higher disease stages (III/IV) compared with those in cases with lower stages (I/II) (44), suggesting a close relationship between tumor-associated pDCs and tumor progression (86). Interestingly, patients with NSCLC who smoke exhibited elevated pDC numbers compared with those of nonsmokers (44). Exploring the role of pDCs in lung cancer may lead to the development of novel therapeutic strategies.

In autoimmunity, pDCs may exhibit both immunogenic and tolerogenic functions according to the development of inflammatory autoimmune disorders (102). Accumulating evidence has suggested that pDCs can aggravate disease development in autoimmune disease, and this immunogenic function appears to be mediated partly by the overproduction of the inflammation-specific cytokine IFN-I (39, 103). IFN-I hyperproduction by pDCs is involved in the pathogenesis of SLE (104) (Figure 2A). Accordingly, the production of IFN-I depends on changes in the functions of mediators derived from autologous pDCs and lesion cells. For example, activation of IFN-I occurs via HMGB1 secreted by necrotic cells and inflammatory cells. HMGB1 then interacts with the receptor for generation of advanced glycation end products, which induces the activation of pDCs via the TLR-9-MyD88 pathway (105).

In addition, IFN-I overproduction may induce feedback regulation to target pDCs or other immune cells. In healthy individuals, pDCs promote the differentiation of immature B cells into IL-10-producing Bregs with stimulation by high concentrations of IFN-α, which subsequently suppresses IFN-α production by pDCs via IL-10 release. In SLE, despite aberrant Breg function, IFN-α overexpression may still result in regulatory feedback between pDCs and Bregs. Thus, altered pDC-Breg interactions contribute to the pathogenesis of SLE (106). IFN-I can also upregulate serum lupus autoantigens, such as Ro52 and laminin-1b, which could influence SLE progression (107, 108). Therefore, analysis of the functions of pDCs in SLE can help to develop new therapeutic strategies.

Interferon I production by pDCs also plays an immunogenic role in other autoimmune diseases. LL37, an antimicrobial peptide that is highly expressed in psoriatic lesions, binds self-DNA to form aggregated and condensed structures that are potent activators of pDCs in vitro. These complexes are delivered to pDCs to trigger TLR-9 expression and local IFN-I production (109). As a result, IFN-I released from pDCs in tissue lesions initiates the autoimmune T-cell cascade, facilitating autoimmunity (110).

In contrast to the immunogenic function of pDCs, increasing evidence has supported that unstimulated or alternatively stimulated pDCs can act as tolerogenic cells in autoimmune disease. Siglec-H is a surface molecule specifically expressed on mouse pDCs. Siglec-H-mediated antigen delivery was found to induce a hyporesponsive state in CD4⁺ T cells, leading to reduced expansion and inhibition of Th cell-dependent immunity (111). In addition, in the disease microenvironment, IL-3 and CD40L can activate pDC precursors, which are able to induce the differentiation of IL-10-producing CD8⁺ Tregs (112–114). In patients with juvenile idiopathic arthritis and cutaneous lupus erythematosus, pDCs can secrete large amounts of granzyme B in response to immunomodulatory cytokines, such as IL-3, IL-10, and IL-21. Moreover, pDC-derived granzyme B suppresses T-cell proliferation in a cell contact-dependent manner, similar to Tregs (115, 116) (Figure 2C). IDO can suppress the antigen-presenting ability of pDCs (117). In addition, studies have demonstrated that IDO can induce tolerogenic pDC function, although the underlying mechanism needs to be evaluated in animal models (42, 118) (Figure 2B).

Plasmacytoid dendritic cell function is tightly regulated in immune disorders by iNKT cells. pDCs are an essential partner of iNKT cells in T1D. Upon viral infection, iNKT cells induce TGF-β-producing pDCs in the pancreatic lymph nodes. These tolerogenic pDCs convert naive anti-islet T cells into Foxp3⁺CD4⁺ Tregs in pancreatic lymph nodes. Tregs are then recruited to pancreatic islets, where they produce TGF-β, which dampens the activity of viral- and islet-specific CD8⁺ T cells, thereby preventing T1D development in animal models (119–121) (Figure 2D).

Plasmacytoid dendritic cells exhibit different functional mechanisms during the development of inflammatory autoimmune disorders. Immunogenic pDC functions contribute to disease pathogenesis, e.g., SLE, through IFN-I production; however, tolerogenic pDCs may promote self-antigen-specific CD4⁺ T-cell tolerance and induce Treg differentiation, as observed in RA and T1D. Further studies of pDCs functional mechanisms in different diseases may facilitate the development of novel therapies.

Dendritic cell-based vaccines against cancer have also been developed during the past two decades. Clinical evidence showed that TAA-derived peptides loaded onto pDCs or CD1c⁺ DCs achieve promising efficacy in patients with melanoma (135, 136). Confronting immune checkpoint inhibitors targeting CTLA4, PD1, and PD-L1 may lead to clinical benefits in patients with various types of cancers, and next-generation DC vaccines are expected be developed by integration of DC-based vaccines with combinatorial immunotherapy regimens (137).

Besides potential therapeutic applications in cancer, pDCs have also been shown to have important properties in autoimmune diseases. For example, pDCs are major immune contributors in lupus via IFN-I overexpression. Early studies have shown that congenic lupus-predisposed mice lack pDCs because of IRF8 deficiency or SLC15A4 mutation. Moreover, the results indicated absence of autoantibodies, reduced lymphadenopathy and splenomegaly, and extended survival. IRF8 and SLC15A4 may therefore be important targets for therapeutic intervention in lupus (40). Notably, both IRF8 and SLC15A4 are upstream molecules of the TLR pathway and are important for IFN secretion. As abnormal pDC activation and deregulated IFN-I production appear to be contributing factors in autoimmune disease pathogenesis, future studies should be performed to determine whether IFN-I blockade or pDC depletion would be an effective method for the treatment of autoimmune diseases (138).

Recent findings of DCs could make us redefine our perception of DC populations. For example, See’s group defined a population of CD123⁺CD303⁺CX3CR1⁺CD33⁺ cells as DC precursors (pre-DCs), which share surface markers with classically defined pDCs and exhibit distinct functional properties. After removal of pre-DCs from the classically defined “pDC” population, the induction of T-cell proliferation and production of T-cell stimulatory ligands by pDCs is decreased (139). Additionally, Villani et al. demonstrated six DC and four monocyte cell clusters using single-cell RNA-sequencing. The authors validated the presence of Axl⁺Siglec6⁺ DCs (AS DCs), which share transcriptional modules with classically defined “pDCs,” but do not secrete IFNα and have stronger capacity to activate T cells (140). To date, pre-DCs and AS DCs have been shown to have similar functions; therefore, further studies are needed to verify their identities. The discovery of these two subtypes improves our understanding of classically defined pDCs, which should be reconsidered based on the antigen presenting and cytokine-secretion functions of pDCs; the taxonomy may also need to be revised accordingly. These concepts are expected to facilitate more precise analyses of DC subset-specific targeting in health and disease.

Plasmacytoid dendritic cells are thought to be involved in the pathogenesis of a variety of diseases. Given the capacity of pDCs to easily switch phenotypes and functions according to disease microenvironmental signals, this plasticity may be harmful when disorders occur in individuals. In this review, we summarized the possible mechanisms of deterioration induced by pDCs. Different immunotherapeutic approaches, as well as combinations with other local or systemic disease therapies, may be required to realize synergistic benefits. Immunotherapy induced by pDCs will cover many nonclassic diseases. However, further clinical trials are necessary to identify the effective dose and criteria for suitable patients.