The clinical success of cell-based immunotherapies has revolutionized treatment of cancer and other diseases by enabling precise and durable tumor targeting. However, while traditional ex vivo engineering of immune cells has demonstrated promise, these approaches are constrained by logistical, economic, and manufacturing challenges that hinder broad clinical adoption. In vivo immune engineering, which directly reprograms immune cells within the patient's body, is emerging as an attractive alternative to overcome these limitations and directly reshape the tumor microenvironment (TME) in situ and restore antitumor immunity. This review surveys current approaches to overcoming them through in vivo delivery platforms and therapeutic constructs to achieve direct in vivo gene editing. We further discuss key safety and efficacy considerations, such as biodistribution, gene expression control, immunogenicity, and tumorigenicity. Finally, we examine early clinical efforts and translational hurdles in bringing in vivo immune engineering strategies to the bedside.