CAR-T and TIL therapies in solid tumors: barriers, clinical lessons, and convergent solutions

Abstract

The approval of lifileucel in 2024 marked an important milestone in oncology as the first cellular therapy authorized for a solid tumor. This milestone stands in sharp contrast to the success of CAR-T cells in hematologic malignancies, where six products have been licensed, and highlights the central challenge that solid tumors remain largely unconquered. At the mechanistic core lies a three-stage framework describing the major barriers encountered by therapeutic T cells in solid tumors, a series of escalating barriers that any therapeutic T cell must overcome to achieve durable tumor control: (1) Access: overcoming stromal and vascular barriers that restrict T-cell infiltration into tumors, (2) Recognition: identifying malignant cells in the setting of antigen heterogeneity and immune evasion, and (3) Persistence: maintaining T-cell function within the immunosuppressive tumor microenvironment. Historically, CAR-T and TIL therapies were viewed in competition, each occupying distinct niches. The field is increasingly adopting a convergent paradigm in which both platforms address a common challenge: overcoming the biological barriers that limit durable responses in solid tumors through complementary engineering and biological strategies. We review the biological obstacles, emerging convergence strategies, and translational frameworks including biomarker-guided patient selection that define this new area. Therapeutic selection may increasingly be guided by a tumor’s dominant biological barriers rather than by platform classification alone.