In vivo CAR-T for solid tumors: facing all the challenges of ex vivo CAR-T and more.

The emergence of in vivo CAR-T technologies has generated considerable excitement as a means of simplifying cellular immunotherapy. However, whether current in vivo CAR-T platforms are truly positioned to succeed in solid tumors remains unclear. We argue that the major limitations of CAR-T therapy in solid tumors arise from a complex interplay between biological barriers and engineering constraints. Although in vivo CAR-T platforms may simplify manufacturing, the delivery strategy itself directly influences which T-cell populations are engineered, the level and duration of CAR expression, cellular phenotype, persistence, and safety. Therefore, in vivo CAR-T therapies do not eliminate the biological barriers that restrict ex vivo CAR-T therapy, including poor trafficking, stromal exclusion, antigen heterogeneity, T-cell dysfunction, and immunosuppressive tumor microenvironment (TME). Consequently, in vivo CAR-T therapies inherit nearly all of the challenges that have restricted ex vivo CAR-T therapy while simultaneously introducing additional limitations related to CAR-T generation, persistence, and controllability. The encouraging results observed in hematologic malignancies and autoimmune diseases may therefore not predict success in solid tumors. Future advances will likely depend less on improving gene delivery and more on establishing mechanisms that support CAR-T infiltration, expansion, and persistence within tumors.