Antigen escape in CAR-T therapy: A tumor microenvironment perspective from hematological to solid tumors.

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.