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International Journal of Bioprinting Bioprinted tumor immune microenvironment

Table 4. Immunotherapy outcomes in bioprinted tumor immune microenvironment model.
Immunotherapy bTIME construct Cells Bioink Outcome
CSF-1 inhibitor (BLZ945) 76 Miniatured brains Macrophages and glioblastoma GelMA Inhibition of tumor cell growth
STAT6 inhibitor cells Decreased macrophage recruitment
(AS1517499) 76 marker, SPP-1
Anti-CTLA-4 79 Core–shell Pancreatic ductal GelMA, alginate Enhanced migration speed and
adenocarcinoma cells, CAFs, directionality of immune cells
splenocytes, T cells, and NK cells
L1CAM CAR-T 104 Disk with channel Neuroblastoma cells in GelMA CAR-T cells showed higher
activation in the bioprinted model
compared to the 2D model
Abbreviations: CAFs, cancer-associated fibroblasts; CAR-T, Chimeric antigen receptor-T cells; CSF-1, colony-stimulating factor 1; CTLA4, Cytotoxic
T-lymphocyte-associated protein 4; GelMA, gelatin methacryloyl; L1CAM, L1 cell adhesion molecule; STAT6, signal transducer and activator of
transcription 6.

5. Conclusion cell and tissue interactions. Second, analyzing the vast
amounts of data generated from complex 3D structures
In this paper, we review the critical aspects of bTIME for is challenging. Third, reproducing tissue-level cell density
immunotherapy research. Several key areas warrant further and stiffness is difficult because bioprinted tissues lack the
investigation and development. 3D bioprinting plays a
crucial role in the development of immunotherapies. microvasculature to supply nutrients, leading to necrosis at
Considering the advantages, limitations, and areas high cell densities. Additionally, degradation proteins from
cells can dissolve the bioink, making it hard to maintain
requiring optimization of this technology, significant the structure and stiffness of the tissue.
advancements can be made in the efficacy evaluation and
personalized design of immunotherapies. Several approaches are proposed to address these
One of the main advantages of 3D bioprinting is its issues. First, imaging challenges can be tackled using
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ability to accurately model the TIME. To create the TIME advanced imaging technologies like CLARITY, optical
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model, it is essential to control the positions of tumor cells, coherence tomography (OCT), and photoacoustic
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immune cells, and stromal cells accurately. In the TIME, imaging. CLARITY makes tissues transparent to enable
these cells exhibit heterogeneity and distinct regions while visualization of 3D structure, while OCT provides high-
being closely associated. This heterogeneity allows the resolution real-time imaging of tissue microstructures,
observation of cancer and immune cells’ migration. This and photoacoustic imaging allows for deep tissue imaging.
capability is particularly useful in observing CAR-T cell Second, analysis challenges can be addressed using
infiltration, specific targeting, and tumor mass changes, artificial intelligence (AI), which can quickly analyze large,
helping to overcome the disappointing efficacy of CAR-T/ complex datasets to identify patterns and provide insights
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NK cells in solid tumors. Additionally, bTIME can into cell behaviors and therapeutic responses. Finally,
recapitulate immunosuppressive environment with the the difficulties in reproducing tissue-level cell density
tumor-protective ECM and immunosuppressive stromal and stiffness can be resolved by optimizing bioinks or
cells, which are challenging in 2D or conventional 3D introducing new materials.
spheroid models. These advantages position 3D bioprinting In conclusion, 3D bioprinting shows great potential
as a crucial predictive model in the development of for immunotherapy development. By accurately modeling
immunotherapies. They provide promising results TIME, it enables precise evaluation of CAR-T cell efficacy
in screening CAR-T cell candidates, more accurately in tumors. With the inclusion of stromal cells, bTIME
predicting their efficacy and safety. Detailed studies of can replicate an immunosuppressive environment. In-
immune–tumor interactions in a controlled environment depth study to overcome immunosuppressive effect on
promote more effective immunotherapy development and immune cells such as cell trafficking can be carried out
reduce dependence on animal models. in the bTIME. Advancements in imaging, AI integration,
However, 3D bioprinting faces several limitations. First, and bioink optimization address current challenges in
high-resolution imaging is challenging in thick bioprinted bioprinting, making 3D bioprinting an essential tool for
TIME structures, making it difficult to accurately observe creating personalized and effective immunotherapies.

Volume 10 Issue 5 (2024) 41 doi: 10.36922/ijb.3988