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International Journal of Bioprinting Bioprinted tumor immune microenvironment

for patients. However, traditional animal models and cells, bioink formulations, and the required structural
two-dimensional (2D) cultures, which have long been complexity. The development of bioprinted TIME (bTIME)
used in tumor immunotherapy research, presenting a models will be detailed, with a focus on their creation and
significant limitation due to difference in circulating the evaluation of immunotherapeutic drug efficacy within
immunosuppressive cytokines like Interleukin-10 (IL-10) these models.
and transforming growth factor (TGF)-β. To overcome
1
these limitations, the in vitro simulation of the TIME 2. Immunotherapy
can facilitate the study of the immune response in tumor
models and the interaction between tumor and immune Immunotherapy is a type of cancer treatment that
cells and can aid in the exploration of the effectiveness harnesses the body’s immune system to fight cancer.
of immunotherapeutic drugs and their mechanisms of Unlike traditional therapies that directly target tumor cells,
action. immunotherapy stimulates or enhances the natural ability
2–4
of the immune system to recognize and destroy cancer
TIME models, especially those created using cells. This approach can provide long-lasting protection
bioprinting technology, offer enhanced fidelity and are against cancer by creating an immune memory, which
closer to the in vivo TIME than traditional 2D culture helps prevent the recurrence of cancer. Immunotherapeutic
models. This is because bioprinting, an advanced form drugs are represented by immune modulators, checkpoint
5
of three-dimensional (3D) modeling, allows for the inhibitors, CAR-T cells, cancer vaccines, etc.
precise placement of cells, extracellular matrix (ECM),
and bioactive molecules to create complex structures that Immune modulators are drugs that modify the immune
closely mimic the human microenvironment in vitro. response to enhance anti-tumor activity. Their mode of
6
This capability addresses the limitations seen with animal action involves targeting various pathways to modulate
models and conventional 2D cultures, enhancing our the immune system and improve its ability to fight cancer.
understanding of cancer pathophysiology and metastasis. Examples of immune modulators include pexidartinib
7
By accurately arranging cells and ECM, bioprinting (Turalio), which targets the colony-stimulating factor 1
provides a realistic representation of the TIME, invaluable (CSF-1) pathway.
14
for advancing cancer therapies, including drug screening, Checkpoint inhibitors are drugs that block proteins used
high-throughput analysis, 8 personalized treatment by cancer cells to evade detection by the immune system.
15
research, and the study of cancer metastasis mechanisms. Checkpoint inhibitors work by targeting checkpoint
10
9
The ability to replicate the intricate interactions within the proteins such as programmed cell death protein 1 (PD-
TIME makes bioprinting a particularly useful technology
for exploring the effectiveness of various immunotherapies 1), programmed death-ligand 1 (PD-L1), and cytotoxic
16
and their mechanisms of action. T-lymphocyte-associated protein 4 (CTLA-4).
The tumor microenvironment (TME) primarily CAR-T cell therapy involves modifying the T cells of
focuses on the interactions between cancer cells and patients to express CARs on their surface. These receptors
various stromal components, including fibroblasts and are designed to recognize specific proteins on cancer cells,
17,18
the ECM, as well as the formation of blood vessels. In enabling the T cells to target and kill the cancer cells.
contrast, the TIME includes not only these elements but However, the success of CAR-T therapy is largely limited
also the dynamic interactions with immune cells. These to non-solid tumors such as leukemia and lymphoma. It
interactions are critical for understanding how tumors has not been proven effective against solid tumors such
evade immune detection and how immunotherapies as breast, lung, and pancreatic cancers, where numerous
can be optimized. Existing studies have mainly focused hurdles, including trafficking and immune suppression,
on bioprinting the TME, with limited reviews on using are known to interfere with the therapy. These challenges
bioprinting to simulate the TIME. 11–13 underscore the need for advanced bioprinted models to
study and overcome the barriers to CAR-T therapy in
This review intends to conduct an in-depth exploration solid tumors.
of the TIME, focusing on how bioprinting methods and
design considerations can significantly advance our Cancer vaccines are designed to stimulate the immune
19
understanding and manipulation of these complex systems. system to recognize and attack cancer cells. These vaccines
The following sections will be covered: immunotherapy, introduce tumor-specific antigens to the immune system,
physiological factors in TIME for bioprinting including prompting it to mount an immune response against cells
immune cells and their social interactions, and ECM. bearing these antigens. This can involve either stimulating
Additionally, this paper reviews the components essential T cells to attack cancer cells or enhancing the production
for bioprinting the TIME, including the sources of immune of antibodies against cancer cells. 20

Volume 10 Issue 5 (2024) 32 doi: 10.36922/ijb.3988