A major function of the immune system is to detect threat from foreign invaders, tissue damage, or
cancer and to mount a counter response that resolves the threat, restores homeostasis, and supplies immunological memory to prevent a second assault. Our increasing understanding of the immune system has opened up numerous avenues for modulating immune responses against
infections,
cancer, and autoimmunity. However, agents used for
immunomodulation have been traditionally administered systemically via bolus injection, leading to unintended consequences by disrupting homeostasis at nontarget sites. Consequently, systemic hyperactivation and hypoactivation can result from bolus administration of immune-activators and
immunosuppressants, respectively. Macroscale
biomaterial scaffolds can instead be placed at the intended target site to provide both localized, controlled release of
immunomodulatory agents and control over local immune cell trafficking and function, potentially maximizing therapeutic efficacy and limiting systemic exposure. These scaffolds have found utility in the area of
cancer immunotherapy, especially in situ
cancer vaccination where controlled release of factors such as
granulocyte-macrophage colony-stimulating factor (
GM-CSF) and the local presentation of
tumor antigen and danger signals lead to the recruitment of immature dendritic cells and facilitate their activation and antigen presentation. These cells eventually migrate into secondary lymphoid organs where they prime
tumor specific T cells for downstream
tumor clearance. Scaffolds can also be used in adoptive T cell
therapy to generate large numbers of potent
antigen specific T cells or
chimeric antigen receptor (CAR) T cells in vitro for subsequent delivery to patients. Macroscale
biomaterial scaffolds have also found utility beyond
cancer immunotherapy and have been developed to promote immune tolerance by regulatory T cell induction and to expedite tissue regeneration. The design of these macroscale
biomaterial scaffolds considers their biocompatibility, biodegradability, mode of delivery, porosity, and kinetics of therapeutic cargo release. Consequently, the numerous approaches that have been developed to fabricate
biomaterial scaffolds are aimed at tuning these parameters to achieve the desired therapeutic outcome. This Account will discuss the use of
biomaterial scaffolds as niches for
immunomodulation and will focus on (1) approaches that have been used to fabricate various
biomaterial systems being employed as niches for
immunomodulation and (2) how these
biomaterial systems have been used to modulate immune responses, specifically in area of
cancer immunotherapy, where we will discuss the role of macroscale
biomaterial scaffolds for in situ vaccination and in vitro T cell expansion. We will also briefly discuss the utility of
biomaterial scaffolds beyond
cancer, drawing examples from tolerance and tissue regeneration.