Comparing DC subsets in solid tumors: what about DC3s?

Dendritic cells (DCs) are critical sentinels of the immune system, serving as indispensable bridges between innate and adaptive immune responses. DCs are a heterogeneous population, with subsets playing specialized roles in immune defense, tolerance, or disease development. Among these, the recently redefined DC3 subset has gained attention for its unique features and potential roles in health and disease. This review focuses on the phenotypic, functional, and developmental diversity of DC subsets-primarily DC3s-and their contributions to cancer. The tumor microenvironment (TME) in solid tumors is characterized by varying degrees of immune cell infiltration, including DCs. Within the TME, DCs play diverse roles, either promoting anti-tumor responses or facilitating immune evasion. Key subsets include conventional type 1 and type 2 DCs (cDC1s and cDC2s), as well as plasmacytoid DCs (pDCs). DC3s share certain features with cDC2s and monocytes but are distinct in their phenotype, function, and ontogeny. Functionally, DC3s can prime and activate T cells, skewing CD4⁺ T cells towards Th17 and stimulating CD8⁺ T cells with a tissue-resident memory phenotype. In cancer, their presence correlates with diverse outcomes depending on the TME: DC3 presence is linked to increased survival in patients with pancreatic ductal adenocarcinoma and oropharyngeal cancer while in non-small-cell lung cancer and melanoma it is associated with immunosuppression. The emerging understanding of DC3s highlights the complexity of DC biology and its relevance to diseases. The dynamic immunomodulatory functions of DC3s open new avenues for developing targeted therapies against cancer and immune-mediated disorders.