Beyond Dendritic Cells: A Cellular Pharmacology Agenda for
mRNA
Cancer Vaccines in Hematologic Malignancies
Fortunato Morabito, Enrica Antonia Martino, Antonella Bruzzese, Nicola Amodio, Santino Caserta, Eugenio Lucia, Virginia Olivito, Caterina Labanca, Francesco Mendicino, Maria Eugenia Alvaro, Ernesto Vigna, Massimo Gentile ABSTRACT
Background
mRNA‐based vaccines are emerging as a promising platform for cancer immunotherapy, including in hematologic malignancies. Current vaccine development has largely focused on antigen selection, mRNA engineering, lipid nanoparticle (LNP) formulation, and combination with established immunotherapies. However, increasing evidence indicates that the cellular and tissue distribution of antigen expression may critically influence the quality and durability of the immune response. In this context, the term “cellular pharmacology” refers to the principle that the pharmacodynamic effect of an mRNA vaccine is shaped not only by the encoded antigen and formulation but also by the cell types in which antigen expression occurs.
Objectives
Here, we propose a cellular pharmacology framework for mRNA vaccines in hematologic malignancies, moving beyond the traditional dendritic‐cell‐centric model and considering antigen expression as a determinant of immune activation, tolerance, and T‐cell exhaustion.
Discussion
Three functionally distinct compartments can be considered: professional antigen‐presenting cells, immunogenic non‐immune cells at the injection site, and tolerogenic tissues, particularly hepatocytes. This tripartite model is intended as a simplified functional framework rather than a complete anatomical or cellular classification. While antigen expression in dendritic cells and other antigen‐presenting cells supports effective T‐cell priming, antigen production by skeletal myocytes and stromal cells may provide a sustained source of antigen for uptake and cross‐presentation. Importantly, myocytes should not be regarded as professional antigen‐presenting cells, but rather as potential antigen‐producing cells whose antigens can be presented by professional APCs. Conversely, hepatic antigen expression may promote peripheral tolerance and impair antitumor CD8+ T‐cell responses. Recent preclinical evidence indicates that microRNA‐guided hepatocyte detargeting may enhance vaccine‐induced immunity and tumor control in experimental models, although its clinical relevance in hematologic malignancies remains to be established. This concept may be particularly relevant in hematologic malignancies, characterized by disseminated disease, chronic antigen exposure, immune dysfunction, and frequent treatment‐related organ vulnerability. We discuss how cellular targeting could be incorporated into mRNA vaccine strategies for lymphomas, acute leukemias, chronic lymphocytic leukemia, and multiple myeloma, as well as into combination approaches with CAR‐T cells, bispecific antibodies, and immune checkpoint inhibitors.
Conclusions
The therapeutic potential of mRNA vaccines in hematologic malignancies may depend not only on the antigen encoded but also on the cellular compartment in which it is expressed. Incorporating tissue biodistribution and cell‐type specificity into vaccine design could represent a new strategy to improve immunogenicity while limiting tolerogenic signals and potentially reducing unwanted tissue exposure. At present, however, hepatocyte detargeting should be considered a promising and testable translational strategy rather than a clinically validated approach. Prospective clinical studies integrating biodistribution, immune correlates, and tissue‐specific antigen expression will be essential to translate this cellular pharmacology concept into clinical practice.