双空间受限组装的 DNA 纳米墙增强肿瘤细胞硬度以提升过继性 T 细胞免疫治疗

Cellular softness acts as a mechanical immune checkpoint, suppressing T-cell mechanosensing and cytotoxicity to drive tumor immune evasion.

However, existing approaches to modulate membrane stiffness lack specificity, limiting targeted therapeutic potential.

Here, we report a dual-spatially confined DNA nanowall assembly strategy to enhance tumor cell stiffness, thereby augmenting the efficacy of adoptive T-cell immunotherapy. In acidic tumor microenvironments, low-pH-triggered membrane-anchored probes (tissue-level confinement) selectively guide the construction of a DNA nanowall on the inner leaflet of the tumor cell membrane (cellular-level confinement).

This biomechanical reprogramming markedly increases tumor rigidity. When combined with adoptive T-cell transfer (ACT) immunotherapy, this strategy restores T-cell mechanical force generation capacity, significantly improving tumor killing outcomes in vitro and in murine solid tumor models.

Our findings underscore the critical role of biophysical signals in cancer-immune interactions, demonstrating that targeting mechanical immune checkpoints can potentiate antitumor immunity.

Furthermore, these discoveries bridge biophysics and oncology, offering a paradigm for precision cancer therapy through the spatiotemporal control of cellular mechanics.