Antigen escape in CAR-T therapy: A tumor microenvironment perspective from hematological to solid tumors
Cet article passe en revue les mécanismes d'échappement antigénique des tumeurs, examine le rôle du microenvironnement tumoral dans ces mécanismes puis aborde les stratégies visant à optimiser les lymphocytes CAR-T pour le traitement des tumeurs solides
Chimeric antigen receptor T-cell (CAR-T) therapy has shown remarkable efficacy in hematologic malignancies, but antigen escape remains a major challenge, especially in solid tumors, where the tumor microenvironment (TME) exacerbates the problem. Mechanisms of antigen escape include antigen loss, epitope masking, lineage switching, and trogocytosis-mediated CAR dysfunction. The TME promotes immune evasion through physical barriers, immunosuppressive cells, and metabolic competition. To overcome these challenges, multi-targeted CAR-Ts, gene editing, epigenetic interventions, and combination therapies have been developed to enhance CAR-T efficacy. Emerging strategies—such as microbial-guided antigen labeling, nanotechnology for metabolic normalization, armored CAR-T secreting TME-modulating agents, and adaptive CAR systems responsive to TME signals—offer new solutions to target “cold” tumors. Future breakthroughs will rely on synergizing dynamic CAR systems for broad antigen coverage, achieved via multi-targeting and non-canonical antigen recognition, with engineered TME remodeling driven by microbial, viral, and immune cell allies, as well as armored CAR-T cells secreting immunomodulators. Combined with metabolic engineering and interdisciplinary innovation, this integrated approach will effectively enable CAR-T cells to orchestrate a multi-faceted anti-tumor ecosystem rather than functioning in isolation.
International Journal of Cancer , résumé, 2025