Plasmacytoid dendritic cells at the forefront of anti-cancer immunity - rewiring strategies for tumor microenvironment remodeling

Sep 21, 2026

Uploaded by Noah

Plasmacytoid dendritic cells (pDCs) are versatile innate immune cells that drive early anti-cancer defense through type I interferon (I-IFN) production triggered by nucleic acid sensing via endosomal Toll-like receptors TLR7 and TLR9. I-IFNs regulate cancer immunosurveillance and immunoediting in a context-dependent manner, and pDCs can also detect cytosolic DNA through the cGAS–STING pathway to promote potent I-IFN independently of TLR7/9. pDCs additionally acquire effector roles by inducing TRAIL and producing granzyme B influenced by cytokines within tumors. Although pDC involvement in cancer immune surveillance remains incompletely defined, their spontaneous activation in tumors is rarely described. In the tumor microenvironment, pDCs often display tolerogenic phenotypes shaped by immunosuppressive cytokines and oncometabolites. Therapeutic approaches currently under study may activate pDCs and disrupt immunosuppressive tumor microenvironment states, potentially improving clinical outcomes. Targeted antibody–drug conjugates against BDCA-2 on tolerogenic tumor-associated pDCs may offer new immunomodulatory strategies for controlling advanced hematologic malignancies and solid tumors. This review integrates recent evidence on pDC biology and pharmacological modulation, emphasizing their prominent role in rewiring anti-cancer immunity.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages31

Reading Time1 h 18 min

AccessFree to download

Abstract

Background

pDC identity and receptors

pDC trafficking and functions

The multifaceted biology of pDC in cancer

Monti etal. J Exp Clin Cancer Res (2024) 43:196 [https://doi.org/10.1186/s13046-024-03121-9](https://doi.org/10.1186/s13046-024-03121-9) Journal of Experimental & Clinical Cancer Research REVIEW Open Access Plasmacytoid dendritic cells at the forefront of anti-cancer immunity: rewiring strategies for tumor microenvironment remodeling Matilde Monti1†, Giorgia Ferrari 1†, Luisa Gazzurelli1, Mattia Bugatti 1, Fabio Facchetti 1 and William Vermi1,2* Abstract Plasmacytoid dendritic cells (pDCs) are multifaceted immune cells executing various innate immunological functions. Their first line of defence consists in type I interferons (I-IFN) production upon nucleic acids sensing through endosomal Toll-like receptor (TLR) 7-and 9-dependent signalling pathways. Type I IFNs are a class of proinflammatory cytokines that have context-dependent functions on cancer immunosurveillance and immunoediting. In the last few years, different studies have reported that pDCs are also able to sense cytosolic DNA through cGAS–STING (stimulator of interferon genes) pathway eliciting a potent I-IFN production independently ofTLR7/9 . Human pDCs are also endowed with direct effector functions via the upregulation of TRAIL and production of granzyme B, the latter modulated by cytokines abundant in cancer tissues. pDCs have been detected in a wide variety of human malignant neoplasms, including virus-associated cancers, recruited by chemotactic stimuli. Although the role of pDCs in cancer immune surveillance is still uncompletely understood, their spontaneous activation has been rarely documented; moreover, their presence in the tumor microenvironment (TME) has been associated with a tolerogenic phenotype induced by immunosuppressive cytokines or oncometabolites. Currently tested treatment options can lead to pDCs activation and disruption of the immunosuppressiveTME, providing a relevant clinical benefit. On the contrary, the antibody–drug conjugates targeting BDCA-2 on immunosuppressive tumor-associated pDCs (TA-pDCs) could be proposed as novel immunomodulatory therapies to achieve disease control in patients with advance stage hematologic malignancies or solid tumors. This Review integrate recent evidence on the biology of pDCs and their pharmacological modulation, suggesting their relevant role at the forefront of cancer immunity. Keywords Plasmacytoid dendritic cells, Cancer, Immune surveillance, Tumor microenvironment, Type I Interferon, Cytotoxic function, Immunometabolism, TLR7/9 agonists, STING agonists, Clinical trials †Matilde Monti and Giorgia Ferrari contributed equally to this work. *Correspondence: William Vermi [william.vermi@unibs.it](william.vermi@unibs.it) 1 Department of Molecular and Translational Medicine, Section of Pathology, University of Brescia, P. Le Spedali Civili 1, 25123 Brescia, Italy 2 Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, USA Background Plasmacytoid dendritic cells (pDCs) are bone marrowderived circulating innate immune cells, identified as CD123+ (IL3R), CD303+ (BDCA-2, also known as C-type lectin CLEC4C), CD304+ (BDCA-4) cells, and negative for lineage markers and CD11c [1]. pDCs home to lymphoid organs and inflamed peripheral tissues by chemotactic stimuli [2], where they execute relevant immune effector and regulatory functions upon nucleic acids sensing through different surface and cytosolic receptors. pDCs have been detected in a wide © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unle

FAQs

How do plasmacytoid dendritic cells initiate anti-cancer immunity?

pDCs initiate early defense by producing type I interferons after sensing nucleic acids through endosomal TLR7 and TLR9 signaling pathways. They can also respond to cytosolic DNA via the cGAS–STING pathway to induce I-IFN independently of TLR7/9.

What additional effector functions do pDCs have in tumors?

In tumor settings, pDCs can upregulate TRAIL and produce granzyme B. These cytotoxic functions are modulated by cytokines abundant in cancer tissues.

Why might pDCs become tolerogenic in the tumor microenvironment, and how can therapy counteract this?

pDCs in the tumor microenvironment can adopt a tolerogenic phenotype driven by immunosuppressive cytokines and oncometabolites. Tested treatments may activate pDCs and disrupt immunosuppressive tumor microenvironment states, and BDCA-2-targeting antibody–drug conjugates are proposed to modulate tolerogenic tumor-associated pDCs.

Sep 21, 2026

Uploaded by Noah