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Dendritic cells (DCs) are central regulators of the immune response by detecting inflammatory signals, aberrant cells, or pathogens. DC‐mediated immune surveillance requires morphology changes to adapt to the physical and biochemical cues of the external environment. These changes are assisted by a dynamic actin cytoskeleton–membrane interface connected to surface receptors that will trigger signaling cascades. In recent years, the development of synthetic immune environments has allowed to investigate the impact of the external environment in the immune cell response. In this direction, the bioengineering of functional topographical features should make it possible to establish how membrane morphology modulates specific cellular functions in DCs. Herein, the engineering of one‐dimensional nanostructured SiO2 surfaces by soft‐nanoimprint lithography to manipulate the membrane morphology of ex vivo human DCs is reported. Super‐resolution microscopy and live‐cell imaging studies show that vertical pillar topographies promote the patterning and stabilization of adhesive actin‐enriched structures in DCs. Furthermore, vertical topographies stimulate the spatial organization of innate immune receptors and regulate the Syk‐ and ERK‐mediated signaling pathways across the cell membrane. In conclusion, engineered SiO2 surface topographies can modulate the cellular response of ex vivo human immune cells by imposing local plasma membrane nano‐deformations.