Heat-Inducible CAR-T Overcomes Adverse Mechanical Tumor Microenvironment in 3D Bioprinted Glioblastoma Model.

Primary malignant brain tumors, particularly glioblastomas (GBMs), remain notoriously difficult to treat due to the failure of conventional therapies and the challenges posed by the immunosuppressive tumor microenvironment and extracellular matrix (ECM) barrier. This study aimedto investigate the interaction between chimeric antigen receptor (CAR) T-cells and the tumor ECM and explore novel strategies to enhance the efficacy of CAR-T-cell therapy.We used digital light processing (DLP)-based 3D bioprinting to construct advanced 3D models thatclosely mimic solid tumors, with modulated stiffness reflecting normal brain and pathological GBM tissue. The models were used to evaluate both standard and heat-inducible CAR-T-cell therapies. Ourresults demonstrated that the heat-inducible CAR-T cells effectively penetrated the stiff tumormicroenvironment, significantly increasing T-cell infiltration and cytotoxicity against tumor cells. Thisindicates the potential of heat-inducible CAR-T cells for treating stiffened GBM. Thispioneering application of 3D bioprinting to model the stiffness of the ECM has provided crucial insightsinto CAR-T cell penetration and tumor cytotoxicity and offers a promising path toward developing moreeffective CAR-T therapies.