Hydrogels as advanced drug delivery platforms for cancer immunotherapy: promising innovations and future outlook

Abstract

Tumor immunotherapy has appeared as a groundbreaking method in cancer therapy, which destroys cancer cells through identification and attack by stimulating the body's immune system. Despite its rapid development, there are serious challenges to overcome. Efficient delivery of the immunotherapeutic cargos to the tumor microenvironment (TME), activation, and systemic adverse reactions have hindered their therapeutic application. Due to their biocompatibility, self-healing ability, and stable localized drug delivery to the tumor niche, hydrogels are regarded as potent delivery platforms. Tailor-made 3D hydrogels from various polymers have shown high drug-loading capacity, which could deliver different immunomodulators to activate effector T cells and enhance immunotherapy efficiency. Injectable hydrogels have also gained significant attention as carriers for tumor vaccines and cell delivery due to their minimal invasiveness encapsulation of various immunotherapeutics, protecting them from degradation and triggering a local immune response. This article reviews recent advances in using hydrogels as immunotherapeutic and cell delivery platforms in cancer immunotherapy, highlighting their ability to overcome the limitations of current delivery systems. In addition, their structure and functional modifications in the development of stimuli-responsive hydrogels, injectable and multifunctional hydrogels are further discussed. Prospects and obstacles in the development of hydrogel-based cancer immunotherapy are also examined.

Keywords: Cancer immunotherapy; Hydrogels; Injectable; Stimuli-responsive; Tumor vaccines.

Fig. 1

Tumor immunity cycle, the process which primarily involves T-cell-mediated cellular immunity, can be enhanced by hydrogels. This sequence includes the following steps: (1) APCs are co-loaded with immunomodulators into the hydrogels. (2) Hydrogels discharge antigens and immunomodulators. (3) APCs absorb and also display tumor antigens. (4) T cells are primed and activated in lymph nodes. (5) T cells circulate and migrate. (6) T cells identify and destroy cancer cells at the tumor site. Reproduced from [6]

Fig. 2

The TME comprises diverse cancerous and non-cancerous cells embedded within a complex extracellular matrix (ECM). It includes various cellular elements such as tumor-associated neutrophils (TANs), NK cells, T-reg cells, MDSCs, mast cells, TAMs, T lymphocytes, mesenchymal stem cells, neutrophils, adipocytes, lymphocytes, pericytes, CAFs. Other immune components contribute to the proliferation and dissemination of tumor cells besides immune system suppression [32]

Fig. 3

The interaction between CAFs and immune cells involves complex signalling. Tumor cells initiate the activation of fibroblasts through various mechanisms. This activation makes fibroblasts diversify into distinct subtypes influenced by specific biochemical and mechanical signals in their surrounding environment. This picture highlights the principal signalling pathways facilitating communication between CAFs and immune cells [53]

Fig. 4

Localized co-administration of CAR-T cells and therapeutic compounds via hydrogels shows potential for treating solid cancers. CAR-T cell treatment is genetically modifying a patient's T cells to produce CAR-T cells that direct them to target cancer cells that have a particular antigen on their surface. Delivering CAR-T cells and other therapeutic compounds encapsulated in a hydrogel at the tumor site locally could potentially overcome some obstacles of solid cancers using CAR-T cell therapy. The hydrogel has the potential to act as a local drug delivery depot system at the tumor site to support synergistic anti-tumor effects between the CAR-T cells and therapeutic compounds. This approach can improve CAR-T cell incorporation, persistence, and immune response against solid tumors challenging microenvironment. Reproduced from [128]

Fig. 5

Fabrication of DNA hydrogel made of two ultra-long DNA chains synthesized through rolling circle amplification (RCA), containing polyaptamers, CpG oligonucleotides (ODN), and G-quadruplexes (G 4). HhaI@TGMS (triglyceride monostearate) nanoparticles were incorporated into the hydrogel to cleave DNA hydrogel in response to the inflammatory environment, releasing individual functional units Represented with permission from [144]