Microenvironmental challenges in dendritic cell immunotherapy for hematologic malignancies

Dendritic cell (DC)-based immunotherapy has emerged as a promising therapeutic strategy for hematologic malignancies owing to its capacity to elicit tumor-specific immune responses. Despite encouraging results from both preclinical and clinical studies, the overall efficacy of DC-based therapies remains limited, primarily due to the immunosuppressive nature of the tumor microenvironment (TME). The TME constitutes a complex network of cellular, molecular, and metabolic factors that impair critical DC functions, including differentiation, maturation, migration, antigen processing, and antigen presentation. In this review, we examine the principal mechanisms by which the TME contributes to DC dysfunction in hematologic malignancies, with particular emphasis on immunosuppressive cells, inhibitory cytokines, hypoxia, metabolic reprogramming, and immune checkpoint pathways. We also highlight recent advances aimed at enhancing the therapeutic efficacy of DC-based interventions, including Toll-like receptor (TLR) agonists, immune checkpoint blockade, metabolic modulation, genetic engineering approaches, optimized antigen-delivery platforms, and strategies to improve DC migration and co-stimulatory signaling. By elucidating the intricate interplay between DC biology and the immunosuppressive tumor milieu, this review provides valuable insights into current challenges and emerging opportunities in the development of more effective DC-based immunotherapies. Addressing TME-mediated barriers may represent a pivotal step toward improving the durability, efficacy, and clinical success of DC-based treatments for hematologic malignancies.