In vivo animal studies have long been a cornerstone of cancer research, but scientists increasingly recognise their limitations in accurately predicting human responses. The primary issue with traditional animal models is that this model is lacking a human-like immune system. Most xenograft models must use immunodeficient mice to prevent rejection of human tumour cells, but this then eliminates crucial tumour-immune interactions.
Additionally, the mouse tissue surrounding the human tumour doesn't accurately represent the human tumour microenvironment (TME), affecting growth patterns, drug responses, and metastatic behaviour. The rapid tumour growth in mice compared to humans and differences in metabolism can also lead to drug efficacy and toxicity discrepancies.

Advancements and Challenges in Animal Models.
To address these limitations, researchers have been developing more sophisticated models:

1) Humanized Mouse Models
These mice are engineered to have components of the human immune system, allowing for a more accurate representation of tumor-immune interactions. Humanised mouse models with human immune system components are already used for cancer research and immunotherapy studies. These models have become increasingly sophisticated and better evaluate the efficacy of immunotherapies, including checkpoint inhibitors like anti-PD-1 antibodies. These models have been used to investigate mechanisms of immunotherapy resistance and assess the safety and efficacy of CAR-T cell therapies

Humanized Mouse Model Advantages: These models can allow for the study of some human tumor-immune interactions and provide some (limited) clinically relevant microenvironment information.

Humanized Mouse Model Limitations: The high cost and technical complexity is a huge limitation as is the incomplete reconstitution of the human immune system. A 2023 review on the topic noted that the immune system in this model is still underdeveloped in several important ways:
1. It lacks fully mature defensive cells that respond quickly to threats.
2. It's missing key proteins (HLA molecules) that help the immune system recognise foreign invaders.
3. It can't effectively produce specialised antibodies to fight specific threats.
4. It's lacking the proper structures (lymph nodes and germinal centres) where immune responses are typically coordinated.
These shortcomings mean the model's immune system doesn't function fully like a human's, which can affect how well it mimics real cancer-immune interactions.

2) Patient-Derived Xenograft (PDX) Models
It is not as advanced overall as the humanized models mentioned above, but it can work with the humanized model. Instead of using established cell lines, PDX models use tumour samples taken directly from patients. This approach better preserves the genetic and histological characteristics of the original tumour. PDX models are beginning to be used within humanized mouse model research, but PDX continues to be used on immunodeficient mice. The most commonly seen research that utilises the PDX model today still includes:
Nude mice (athymic, lacking T cells)\
NOD/SCID mice (lacking T and B cells, with reduced NK cell activity)
NSG mice (lacking T, B, and NK cells most severely immunodeficient)

PDX advantages:
Maintain the histological and molecular characteristics of the original human tumour
Preserve tumour heterogeneity
Provides a platform for developing more advanced personalised medicine and drug screening

PDX limitations:
Lack of a fully functional human immune system
Potential for mouse stroma to replace human stroma over time
Variable engraftment rates depending on tumour type

3) Genetically Engineered Mouse Models (GEMMs)
These mice are genetically modified to develop tumours more closely mimic human cancer progression, including interactions with the native microenvironment. This model has been around for some time and represents a significant advancement in cancer research, offering several key advantages over traditional xenograft and cell line models.

GEMMs advantages:
Develop de novo tumours in a natural immune-competent microenvironment
Closely mimic histopathological and molecular features of human cancers
Display genetic heterogeneity similar to human tumours
Allow for spontaneous progression toward metastatic disease
Capture both tumour cell-intrinsic and cell-extrinsic factors in cancer development

GEMMs limitations:
May not fully replicate the genetic complexity of human tumours
Can be time-consuming and expensive to develop

Conclusion
While each model has its strengths, hybrid humanized PDX models are emerging as a highly promising approach to in vivo research. These models will combine the benefits of PDX (maintaining tumour characteristics) with a humanized immune system (of the future, which hopefully has a complete immune system), allowing for the more accurate evaluation of immunotherapies and tumour-immune interactions.
The choice of the current model depends on the specific research question and stage of drug development. For early-stage research and mechanistic studies, GEMMs may be preferred. For later-stage drug development and personalised medicine approaches (if there is adequate funding), humanized PDX models are increasingly seen as the most advanced option, balancing maintaining tumour characteristics and providing some degree of a human-like immune environment.

Study Support
When evaluating in vivo studies, readers could look for the type of animal model used. To save time, search the article for key terms such as:

"Humanized" (mice with human immune system components)
"PDX" (Patient-Derived Xenograft)
"GEMM" (Genetically Engineered Mouse Model)

Descriptions of how the model compares to human cancer might result in phrases like:
"Mimics human tumor biology."
"Replicates human immune interactions."
"Similar to human cancer progression."

Remember: The most commonly seen research that utilises the PDX model today still includes:
Nude mice (athymic, lacking T cells)\
NOD/SCID mice (lacking T and B cells, with reduced NK cell activity)
NSG mice (lacking T, B, and NK cells most severely immunodeficient)

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