From failure to fate: Pressure-driven exhaustion in solid-tumor CAR T-cell therapy

Chimeric antigen receptor (CAR) T-cell therapy has achieved remarkable and durable responses in hematologic malignancies, but its efficacy in solid tumors remains limited and frequently transient. In this Review, we propose that interacting tumor barriers divert persistently engaged CAR-T cells toward dysfunctional and exhausted states. Defective trafficking, antigen heterogeneity, incomplete tumor clearance, metabolic deprivation, stromal exclusion, immunosuppressive cellular networks, inhibitory cytokines, chronic CAR signaling, and manufacturing-imprinted stress collectively shape the stimulation history and functional trajectory of CAR T-cells. Mechanistically, these pressures converge on NFAT-AP-1 imbalance, TOX/TOX2 and NR4A activation, mitochondrial dysfunction, and exhaustion-associated epigenetic remodeling. This process creates a clinically relevant continuum between TCF1-positive progenitor-exhausted cells that retain self-renewal and checkpoint-responsive proliferative potential, and terminally exhausted cells with limited regenerative capacity. Building on this failure-pressure-fate model, we propose a mechanism-informed therapy framework that relates dominant failure mechanisms and residual CAR T-cell plasticity to potential intervention priorities. This approach may help match combination strategies to the dominant tumor pressure and CAR T-cell state, including stromal remodeling, metabolic engineering, cytokine armoring, checkpoint modulation, epigenetic intervention, and remanufacturing. Overall, this Review provides a fate-based framework for designing next-generation CAR T-cell therapies capable of achieving durable control in solid tumors.