Viscoelasticity reprograms T cell metabolism for TCR-T cell manufacturing and therapy

ABSTRACT: Adoptive T cell receptor (TCR)–based immunotherapy offers a powerful strategy to target solid tumors through recognition of either cell surface antigens or intracellular tumor antigens. However, the ex vivo generation of metabolically fit, durable T cells capable of sustained function in the immunosuppressive solid tumor microenvironment remains a major bottleneck. While dendritic cell–based antigen presentation can provide physiological activation signals, its clinical translation is limited by donor variability, poor scalability, uncontrolled paracrine signaling, and the risk of T cell exhaustion. Here we develop synthetic viscoelastic activating cells (SynVAC)—a class of artificial antigen-presenting cells (aAPCs) whose stress-relaxation kinetics are independently and precisely tuned while maintaining constant stiffness and defined densities of peptide–major histocompatibility complex (pMHC) and co-stimulatory ligands. SynVAC-pMHC offers a well-defined and scalable platform that outperforms monocyte-derived dendritic cells (moDCs) to enrich antigen-specific CD8+ T cells. Particularly, fast-relaxing SynVAC-pMHC amplifies TCR signaling and mTOR activity, drives mitochondrial remodeling, and programs antigen-specific T cells toward an energetically favorable metabolic state with enhanced stem-like properties. Furthermore, TCR-T cells expanded using fast-relaxing SynVAC-pMHC exhibit superior persistence and durable antitumor activity in melanoma and ovarian cancer models. Together, these results establish cell-mimetic viscoelasticity as a key biophysical cue governing T cell metabolism and differentiation, and provide a scalable, fully synthetic strategy to manufacture potent TCR-T cells for solid tumor therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE324103 | GEO | 2026/09/03

REPOSITORIES: GEO