Reserpine enhances dendritic cell cross-presentation and strengthens CD8⁺ T cell-mediated antitumor immunity

Dendritic cell (DC) cross-presentation is essential for priming tumor-reactive CD8⁺ T cells, but small-molecule approaches to enhance this process remain limited. A flow-cytometry-based natural-product screen identified reserpine (Res) as a candidate enhancer of antigen cross-presentation. Res increased surface H-2K^b-SIINFEKL presentation in MutuDC cells and Flt3L-derived bone marrow DCs, and Res-conditioned DCs promoted OT-I CD8⁺ T-cell IFN-γ production and antigen-specific B16-OVA tumor cell killing. In vivo, Res reduced B16 melanoma and MC38 colon tumor growth and improved anti-PD-1 responses in the B16 model. Anti-CD8 and anti-CD11c treatment attenuated Res-associated tumor control, consistent with contributions from CD8⁺ T cells and CD11c⁺ cells. Mechanistically, the effect persisted when Res was added after OVA pulsing and washing, and Res did not significantly alter direct peptide loading, fluorescent OVA uptake, or DQ-OVA-reported uptake-associated proteolysis under the tested conditions. Res increased 20S proteasome activity, and MG132, epoxomicin and bortezomib reduced Res-enhanced cross-presentation, supporting the involvement of a proteasome-dependent antigen-processing step. These findings identify Res as an immunopharmacological modulator of DC cross-presentation with potential relevance to antitumor immunotherapy.