Rational design of immune-cell-homing macroporous hydrogels for enhanced dendritic cell recruitment and cancer vaccination

Macroporous biomaterials have emerged as a promising platform for in situ cancer vaccination because they can create localized immune niches that recruit, activate, and program dendritic cells (DCs) more effectively than traditional soluble vaccines. However, the immune-cell homing profile of these materials remains difficult to rationally control because key physical parameters-stiffness, viscosity, and pore size-are often inherently coupled. To overcome this challenge, we engineered an alginate-based macroporous hydrogel in which these properties were independently tunable, enabling a systematic investigation of how each dimension shapes DC recruitment and downstream antitumor immunity. The resulting design space revealed a striking synergy: hydrogels combining high stiffness, high viscosity, and large interconnected pores generated the most favorable immune microenvironment, recruiting 1.6-fold more DCs and markedly enriching the cDC1 subset associated with efficient cross-presentation. Large-pore hydrogels supported deeper cellular infiltration and increased MHC II expression, while high-viscosity formulations enhanced cell retention within the scaffold. Although softer matrices facilitated early migration in vitro, stiffer gels promoted superior DC proliferation, survival, and release, revealing a two-phase mechanism in which initial recruitment and sustained persistence are governed by distinct material properties. When loaded with GM-CSF, OVA, and CpG, the optimized hydrogel induced the strongest SIINFEKL-specific CD8⁺ T-cell expansion and achieved significantly delayed tumor progression in prophylactic E.G7-OVA challenge, outperforming all other formulations and soluble controls. These findings establish a mechanistic framework for engineering macroporous hydrogels as programmable immune niches and demonstrate that precise decoupling of material mechanics and pore architecture can amplify vaccine potency in vivo. This work advances the rational design of biomaterial-based cancer vaccines and highlights the importance of material-immune cell crosstalk in generating durable antitumor immunity. AI-assisted text generation (ChatGPT) was used solely for language refinement of this abstract.