Pimozide enhances antigen cross-presentation and promotes cytotoxic CD8+ T cell immunity by stimulating dendritic cells
- 1Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba , ,
Abstract
The activation of cytotoxic CD8 ⁺ T cells requires antigen presentation in the context of major histocompatibility complex class I (MHC-I). While endogenous antigens can directly access this pathway, the priming of CD8 ⁺ T cells against exogenous antigens—such as those derived from tumors or internalized pathogens—depends on dendritic cell (DC)-mediated antigen cross-presentation. Strategies capable of enhancing DC cross-presentation are therefore of considerable interest for the development of next-generation immunotherapies. Here, we demonstrate that pimozide, a clinically approved antipsychotic with reported antitumoral and immunomodulatory properties, acts as a pharmacological enhancer of antigen cross-presentation. We show that pimozide-treated DCs display improved cross-presentation of soluble antigens, leading to stronger CD8 ⁺ T cell activation and proliferation in vivo , enhanced IFN-γ production by antigen-specific CD8 ⁺ T cells in vitro , and augmented cytotoxic T lymphocyte responses in vivo . Mechanistically, pimozide reshapes antigen-processing pathways in DCs by increasing reactive oxygen species production and altering endosomal physiology, thereby creating a biochemical environment that favors antigen cross-presentation. Moreover, pimozide treatment reduces STAT5 levels in DCs, and pharmacological inhibition of STAT5 with an independent inhibitor recapitulates the enhancement of cross-presentation and CD8 ⁺ T cell activation, suggesting STAT5 signaling as a mediator of this effect. Together, these findings reveal an unrecognized immunomodulatory activity of pimozide on DCs and establish a conceptual framework for the pharmacological repositioning of small molecules to reprogram DC function. This work ultimately opens new avenues for amplifying cytotoxic CD8 ⁺ T cell immunity in the context of next-generation cancer immunotherapies.
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BibTeX
@article{palacios2026pimozide,
title = {{Pimozide enhances antigen cross-presentation and promotes cytotoxic CD8+ T cell immunity by stimulating dendritic cells}},
author = {Luz María Palacios and Nicolás Daniel Dho and Cintia Liliana Araujo Furlán and Guadalupe López Menichetti and Federico Ruiz Moreno and Laura Guantay and Sofía Daiana Castell and María Esperanza Felici and Gastón Soria and Belkys Maletto and María Inés Crespo and Gabriel Morón},
journal = {Frontiers in immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1946712},
url = {https://europepmc.org/article/PMC/PMC13668838},
note = {CC BY},
}
RIS
TY - JOUR
TI - Pimozide enhances antigen cross-presentation and promotes cytotoxic CD8+ T cell immunity by stimulating dendritic cells
AU - Luz María Palacios
AU - Nicolás Daniel Dho
AU - Cintia Liliana Araujo Furlán
AU - Guadalupe López Menichetti
AU - Federico Ruiz Moreno
AU - Laura Guantay
AU - Sofía Daiana Castell
AU - María Esperanza Felici
AU - Gastón Soria
AU - Belkys Maletto
AU - María Inés Crespo
AU - Gabriel Morón
PY - 2026
DA - 2026/10/01
JO - Frontiers in immunology
DO - 10.3389/fimmu.2026.1946712
UR - https://europepmc.org/article/PMC/PMC13668838
AB - The activation of cytotoxic CD8 ⁺ T cells requires antigen presentation in the context of major histocompatibility complex class I (MHC-I). While endogenous antigens can directly access this pathway, the priming of CD8 ⁺ T cells against exogenous antigens—such as those derived from tumors or internalized pathogens—depends on dendritic cell (DC)-mediated antigen cross-presentation. Strategies capable of enhancing DC cross-presentation are therefore of considerable interest for the development of next-generation immunotherapies. Here, we demonstrate that pimozide, a clinically approved antipsychotic with reported antitumoral and immunomodulatory properties, acts as a pharmacological enhancer of antigen cross-presentation. We show that pimozide-treated DCs display improved cross-presentation of soluble antigens, leading to stronger CD8 ⁺ T cell activation and proliferation in vivo , enhanced IFN-γ production by antigen-specific CD8 ⁺ T cells in vitro , and augmented cytotoxic T lymphocyte responses in vivo . Mechanistically, pimozide reshapes antigen-processing pathways in DCs by increasing reactive oxygen species production and altering endosomal physiology, thereby creating a biochemical environment that favors antigen cross-presentation. Moreover, pimozide treatment reduces STAT5 levels in DCs, and pharmacological inhibition of STAT5 with an independent inhibitor recapitulates the enhancement of cross-presentation and CD8 ⁺ T cell activation, suggesting STAT5 signaling as a mediator of this effect. Together, these findings reveal an unrecognized immunomodulatory activity of pimozide on DCs and establish a conceptual framework for the pharmacological repositioning of small molecules to reprogram DC function. This work ultimately opens new avenues for amplifying cytotoxic CD8 ⁺ T cell immunity in the context of next-generation cancer immunotherapies.
SN - 1664-3224
ER -