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

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, T‑cell activation requires the coordinated integration of biochemical cues and physical properties of the antigen‑presenting interface, and the mechanistic basis by which these microenvironmental parameters regulate T‑cell metabolic programming remains poorly defined. Here we develop synthetic viscoelastic activating cells (SynVAC)—a class of artificial antigen-presenting cells (aAPCs) whose stress-relaxation kinetics are independently and precisely chemically 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.