Rewriting the dendritic cell code in cancer-from subset identity to immunotherapeutic design.

Dendritic cells (DCs) are central orchestrators of antitumor immunity, bridging innate sensing with adaptive T-cell responses. This review dissects the developmental pathways and functional specializations of diverse DC subsets-including cDC1, cDC2, pDCs, DC3s, tDCs, moDCs, and emerging RORγt antigen-presenting cells (APCs)-and explores how the tumor microenvironment (TME) dynamically reprograms these cells. Immunosuppressive cytokines, metabolic stress, hypoxia, and altered lipid metabolism can induce tolerogenic phenotypes such as mregDCs and ISG DCs, dampening antigen presentation and T-cell activation. We detail how specific DC subsets interact with the TME-either reinforcing immune evasion or promoting antitumor immunity-depending on their transcriptional states and spatial organization. Emphasis is placed on recent findings from spatial transcriptomics and single-cell studies that reveal key DC-T cell niches critical for immune control. Furthermore, we evaluate current and emerging therapeutic strategies that aim to restore DC functionality or exploit their antigen-presenting capabilities, including mRNA vaccines, receptor-targeted delivery, CD40 agonists, and in situ cellular reprogramming. By integrating mechanistic insights with clinical advances, this review underscores the potential of context-aware, subset-specific DC interventions to overcome immune suppression and enhance cancer immunotherapy. Impact statement By dissecting the complexity and plasticity of dendritic cell subsets in cancer, our work offers novel insights into their reprogramming by the tumor microenvironment and therapeutic exploitation, paving the way for next-generation, context-aware immunotherapies.