Hydrogel systems for spatiotemporal controlled delivery of immunomodulators: engineering the tumor immune microenvironment for enhanced cancer immunotherapy

Abstract

Tumor immunotherapy, modulating innate and adaptive immunity, has become an important therapeutic strategy. However, the tumor immune microenvironment's (TIME) complexity and heterogeneity challenge tumor immunotherapy. Hydrogel is a hydrophilic three-dimensional (3D) mesh structure with good biocompatibility and drug release control, which is widely used in drug delivery, agriculture, industry, etc. Hydrogels loaded with immune cells, cytokines, immune checkpoint inhibitors, and anti-tumor drugs can achieve targeted delivery and ultimately activate the immune response in the TIME. In this review, we will summarize the components of the TIME and their immune effects, the emerging immunomodulatory agents, the characteristics and functions of hydrogels, and how hydrogels regulate innate and adaptive immune cells in the TIME.

Keywords: adaptive immunity; hydrogel; immunomodulator; innate immunity; tumor immune microenvironment.

FIGURE 1

Classification chart of hydrogels. This figure introduces the advantages of hydrogels as biomaterials and summarizes three main classification methods of hydrogels, including classification by component source, by binding and crosslinking methods, and by the response to external stimuli. The figure is made with Biorender (https://biorender.com/).

FIGURE 2

Delivery of DCs based on hydrogels in the TIME. DCs are encapsulated in the hydrogels and then released into the TIME. DCs released into the TIME can carry out antigen capture, processing and presentation, thus stimulating the anti-tumor immune function of T cells. DCs can also co-mediate immune response with NK cells and macrophages, while inhibiting immunosuppressive components in the TIME, such as Tregs. The figure is made with biorender (https://biorender.com/).

FIGURE 3

The sketch map of IFN-α2b hydrogels combined with T cell transfer and low-dose irradiation (LDI) in the treatment of gastric cancer. First, LDI was used in the MKN-45 xenografted nude mice model, then T cells were injected in the mice model, followed by IFN-α2b-loaded hydrogels (Gel-IFN). Finally, the enhanced infiltration of T cells and reduced tumor volume were observed. Modified from ref. Liu et al. (2020). The figure is made with biorender (https://biorender.com/).