Hydrogel presents as foreign material to the host and participates in immune responses, which skew the biofunctions of immunologic loads (antigen and adjuvants) during in situ DC priming. This study aims to investigate the effect of the hydrogel made from different polysaccharides on macrophage (RAW264.7) activation and DC (JAWSII) modulation. We adopted polysaccharides of different sugar chemistry to fabricate hydrogels. Hyaluronate (HA), glycol chitosan (GC) and dextran (DX) were functionalized with vinyl sulfone and chemically cross-linked with dithiothreitol via thiol-click chemistry. We found that HA reduced macrophage adhesion and activation on the hydrogel surface. GC and DX promoted M1 polarization in terms of higher CCR7 expression and TNF-α, IL-6 production. In terms of DC engagement, GC promoted antigen uptake by JAWSII and all hydrogels promoted antigen presentation on MHC-I molecules. GC and DX favoured the generation of immunogenic DC while accommodating immunostimulatory functions of IFN-γ and polyI:C or LPS during co-incubation. Particularly, the co-incubation of IP with GC promoted CCR7 expression on JAWSII. Conversely, HA was more appropriate for the construction of a tolerogenic DC priming platform. We observed that HA did not induce co-stimulatory markers expression on DC but suppressed the action of LPS in inducing TNF-α generation. Moreover, when immunosuppressive cytokines, IL-10 and TGF-β were added, cytokines’ immunosuppressive action was amplified by hydrogel bedding, HA, GC and to a less extent DX in suppressing LPS-induced IL-6 generation from JAWSII. We concluded that HA is preferable for tolerogenic DC development while minimizing the macrophage response in conferring foreign body response, whereas DX and GC are more appropriate for immunogenic DC development. This study demonstrates the potential of polysaccharides in conferring in situ DC priming together with antigen and adjuvant loads while addressing the tradeoff between the foreign body responses and DC engagement by selecting appropriate polysaccharides for the hydrogel platform construction.