Tissue-resident memory CAR T cells with stem-like characteristics display enhanced efficacy against solid and liquid tumors

Chimeric antigen receptor (CAR) T cells demonstrate remarkable success in treating hematological malig-nancies, but their effectiveness in non-hematopoietic cancers remains limited. This study proposes enhancing CAR T cell function and localization in solid tumors by modifying the epigenome governing tis-sue-residency adaptation and early memory differentiation. We identify that a key factor in human tissue -resi-dent memory CAR T cell (CAR-TRM) formation is activation in the presence of the pleotropic cytokine, trans-forming growth factor (3 (TGF-(3), which enforces a core program of both "stemness"and sustained tissue residency by mediating chromatin remodeling and concurrent transcriptional changes. This approach leads to a practical and clinically actionable in vitro production method for engineering peripheral blood T cells into a large number of "stem-like"CAR-TRM cells resistant to tumor-associated dysfunction, possessing an enhanced ability to accumulate in situ and rapidly eliminate cancer cells for more effective immunotherapy.