2025.10.11
Plasmacytoid dendritic cells (pDCs) represent a specialized subset of dendritic cells originally celebrated for their extraordinary capacity to produce vast amounts of Type I interferons (IFN-I) upon sensing viral threats, thereby bridging innate and adaptive immunity[1][2]. However, their role within the complex ecosystem of solid tumors has unveiled profound duality—balancing between immune suppression and immune activation. Here, we dissect how these enigmatic cells function as double-edged swords in cancer immunology.
Upon infiltration into the TME—observed in diverse cancers including hepatocellular carcinoma (HCC), multiple myeloma (MM), intrahepatic cholangiocarcinoma, and colon cancer[3][4][5][6]—pDCs often undergo functional reprogramming. Instead of priming antitumor immunity, they adopt a tolerogenic phenotype that actively suppresses effector responses[7][8].
1.Direct Tumor Support: In multiple myeloma, pDCs interact with malignant cells in the bone marrow niche, directly enhancing tumor growth while blunting NK and T cell-mediated cytotoxicity[4]. Similarly, ligand-receptor crosstalk between pDCs, mesothelial cells, and tumor cells creates a metastatic niche favoring immune evasion[9].
2.Inhibition of Adaptive Immunity: Tumor-infiltrating pDCs display an "exhausted" phenotype marked by upregulated inhibitory receptors[8]. This dysfunction diminishes their antigen-presenting capacity and instead promotes regulatory T cell (Treg) activity and myeloid-derived suppressor cell (MDSC) recruitment[10][11].
3.Metabolic Reprogramming: Through enzymes like CD73, pDCs contribute to adenosine accumulation—a key immunosuppressive metabolite—extinguishing cytotoxic T lymphocyte (CTL) responses[12][13].
Clinically, high pDC density frequently correlates with poor prognosis[14][9][6], cementing their identity as architects of an immunosuppressive TME.
Despite their immunosuppressive reprogramming in chronic tumor settings, pDCs retain latent immunostimulatory machinery, making them tantalizing targets for therapy:
1.Interferon-Driven Tumor Control: IFN-α secreted by activated pDCs can directly induce tumor cell apoptosis and recruit cytotoxic immune cells[14][2][15]. In vaccine settings, TLR7/8-stimulated pDCs amplify CD8+ T cell responses and dendritic cell cross-priming[10][16][17].
2.Repolarizing the TME: Strategies combining immunomodulators (e.g., TLR agonists like R837 or COX-2 inhibitors) and nanomaterials successfully convert tolerogenic pDCs into IFN-I-producing effectors. This reprograms "cold" TMEs to "hot," characterized by increased CTLs, M1 macrophages, and stimulatory cytokines (e.g., IFN-γ, IL-12)[18][19][20][21][22][23].
3.Adjuvant Potential: Engineered pDCs from hematopoietic stem cells demonstrate preclinical promise as cell-based vaccines, restoring antigen presentation and reinvigorating antitumor T cells[24].
The dichotomy of pDCs in tumors embodies the broader tension within cancer immunology—between immune escape and immune surveillance. While the immunosuppressive axis helps tumors evade destruction, therapeutic reactivation of pDC-mediated immunity holds immense translational value[8][21][23]. Success will hinge on precisely rewiring pDC function spatially (e.g., using nanomaterials for targeted delivery) and temporally (e.g., combining with checkpoint blockade or chemotherapy).
By exploiting the dual nature of pDCs—suppressors that can be forced into sentinels—the future of immuno-oncology may unlock revolutionary combination strategies to flip the TME from foe to friend[7][15][25].
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14. Monti, Matilde et al. “Impaired activation of plasmacytoid dendritic cells via toll-like receptor 7/9 and STING is mediated by melanoma-derived immunosuppressive cytokines and metabolic drift.” Frontiers in immunology vol. 14 1227648. 3 Jan. 2024, doi:10.3389/fimmu.2023.1227648
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16. Lim, King Hoo et al. “TLR4 sensitizes plasmacytoid dendritic cells for antiviral response against SARS-CoV-2 coronavirus.” Journal of leukocyte biology vol. 115,1 (2024): 190-200. doi:10.1093/jleuko/qiad111
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23. Peng, Haiheng et al. “Dual-targeting Aggregation-induced emission polymer micelles mediate immunogenic sonodynamic therapy for Tumor cell growth inhibition and macrophage reprogramming.” Acta biomaterialia vol. 195 (2025): 321-337. doi:10.1016/j.actbio.2025.01.065
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