Immunotherapy is at the forefront of cancer treatment. The advent of numerous novel approaches to cancer immunotherapy, including immune checkpoint antibodies, adoptive transfer of CAR (chimeric antigen receptor) T cells and TCR (T cell receptor) T cells, NK (natural killer) cells, T cell engagers, oncolytic viruses, and vaccines, is revolutionizing the treatment for different tumor types. Some are already in the clinic, and many others are underway. However, not all patients respond, resistance develops, and as available therapies multiply there is a need to further understand how they work, how to prioritize their clinical evaluation, and how to combine them. For this, animal models have been highly instrumental, and humanized mice models (i.e., immunodeficient mice engrafted with human immune and cancer cells) represent a step forward, although they have several limitations. Here, we review the different humanized models available today, the approaches to overcome their flaws, their use for the evaluation of cancer immunotherapies, and their anticipated evolution as tools to help personalized clinical decision-making.

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