The Jackson Laboratory highlighted how next-generation immuno-oncology modeling platforms aim to better reflect the tumor microenvironment for therapy development. The focus is on improving translation from in vitro activity to clinical outcomes by incorporating more of the in vivo context that is missing in simplified preclinical systems. In an Innovation Spotlight, the discussion centers on “humanized” mouse approaches—highly immunodeficient mice engineered to support human immune cell populations following engraftment of cord blood-derived HSCs or PBMC. The article notes that immune activation dynamics, bioavailability differences, and systemic toxicities such as cytokine-related effects can vary across patients and may be inadequately captured in conventional models. The piece also points to a newly released platform, S15-DKO, described as expressing multiple human growth factors while being deficient in mouse MHC class I and II to reduce xenogeneic graft-versus-host disease risk. For drug developers, the platform upgrade is positioned as a way to improve mechanistic testing of immune interactions before moving into patients.