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Engrafted with components of a human immune system and subsequently implanted with tumor tissue from cell lines or in the form of patient\u2010derived xenografts, the HM provides a unique platform in which the tumor microenvironment (TME) can be evaluated in vivo. This model may also be beneficial in the assessment of potential cancer treatments including immune checkpoint inhibitors. However, to maximize its utility, researchers need to understand the critical factors necessary to ensure that the tumor immune interactions in the HM are representative of those within cancer patients. In most current HM models, the human T cells residing in the HM are educated in a murine thymus, allogeneic to implanted tumor tissue, and\/or alloreactive to mouse tissues, making their interaction and reactivity with tumor cells suspect. There are several strategies underway to harmonize the immune\u2010tumor environment in the HM. 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