Cover: The relevance of immunocompetent models has significantly increased in the preclinical space as more immunotherapy-based drugs approach the clinic. Such models, however, do not faithfully reproduce the tumor heterogeneity observed in patients, a key aspect that dictates how cancer interacts with the surrounding microenvironment. In this issue, DiMarco and Maddalo discuss the strategies and the protocols established so far to fill this gap in the field of in vivo preclinical modeling. Cover image provided by the authors. Created using BioRender. com.