Targeting Dendritic Cells in Cancer Immunotherapy: From Immune Priming to Tumor Microenvironment Reprogramming

Dendritic cells (DCs) are specialized antigen-presenting cells that shape antitumor immunity by integrating antigen uptake, processing, presentation, co-stimulation, and cytokine-mediated T-cell instruction. Their function is therefore critical for generating tumor-specific T-cell responses and may influence responsiveness to immune checkpoint inhibitors. Although early ex vivo DC vaccines established feasibility, safety, and immunogenicity, clinical efficacy has been heterogeneous. Sipuleucel-T demonstrated an overall-survival benefit in metastatic castration-resistant prostate cancer, whereas DCVax-L produced encouraging but methodologically debated survival signals in glioblastoma. More recently, individualized neoantigen mRNA vaccination combined with pembrolizumab has shown durable recurrence-free survival benefit in resected high-risk melanoma. This review examines the biological rationale for DC-directed immunotherapy, tumor-induced DC dysfunction, next-generation DC platforms, in vivo DC targeting, DC-derived extracellular vesicles, negative and controversial clinical evidence, and rational combinations with checkpoint blockade and tumor-microenvironment-modulating strategies. The field is evolving from the use of DCs as cellular vaccine vehicles toward programmable immune-priming approaches that integrate antigen quality, DC functional state, spatial organization, and tumor microenvironment features.