Fibrin Gel-Induced YAP Inactivation/MafG Derepression Elicits CAR T Cell Stemness

CAR T cell therapy has revolutionized hematologic cancer treatment but remains ineffective in most solid tumors. Acting downstream of TCR signaling, proliferation and differentiation programs are integrated to sustain T cell homeostasis. This coupling drives premature exhaustion and limits persistence of manufactured CAR T cells. Stem cell-like CAR T cells (stem-CAR T), capable of self-renewal and long-term cytotoxicity, represent a promising alternative. However, scalable production methods are presently limited.

In a new Immunity study, Lv et al. demonstrate that 3D fibrin gels deliver mechanical signals that decouple proliferation from differentiation, enabling scalable expansion of stem-CAR T cells (1). These cells display enriched T_SCM phenotypes, elevated NANOG, SOX2, and TCF1, and reduced exhaustion markers. Functionally, they sustain cytolytic activity, robust cytokine secretion, and superior tumor clearance across serial assays. In mouse models of colorectal cancer, pancreatic ductal adenocarcinoma, and glioblastoma, stem-CAR T cells effectively infiltrated tumors, maintained cytotoxicity, and prolonged survival. Mechanistic studies identified a β2 integrin-14-3-3 zeta-YAP-MafG signaling axis that drives stemness gene expression, establishing a clinically relevant strategy to generate potent stem-CAR T cells for therapeutic applications in resistant solid tumors.

GeneTex is committed to developing antibodies that facilitate cancer biology and immunology research, including the MAFG antibody (GTX114541), 14-3-3 zeta antibody (GTX101075) and p73 antibody [5B429] (GTX46123) cited in this article. To learn more about GeneTex’s antibodies and other reagents, please click on the individual reagent links and visit the GeneTex website.