Adapting CAR T-cell therapy for glioblastoma to the post-surgical immunosuppressive microenvironment

Glioblastoma (GBM) harbors a profoundly immunosuppressive microenvironment that blunts chimeric antigen receptor (CAR) T-cell therapy. Here, we implemented strategies to reprogram the resection-induced tumor microenvironment (TME) and support CAR T-cell activity. In SB28 and CT2A murine GBM, resection rapidly remodeled the TME, evidenced by TREM2 upregulation across myeloid populations and T-cell exhaustion. Delivery of TREM2 CAR T cells into the resection cavity depleted TREM2⁺ myeloid cells and recruited activated neutrophils. Co-administration of TREM2 and GD2 CAR T cells enhanced survival and reduced exhaustion of both GD2 CAR and endogenous T cells. Additional checkpoint blockade altered CAR T-cell phenotype but did not improve survival. Finally, neoadjuvant GD2 CAR T-cell delivery outperformed adjuvant administration, preserving GD2 CAR T cell effector function and promoting a proinflammatory TME. Collectively, these findings establish TREM2⁺ myeloid cells as critical regulators of perioperative CAR T-cell efficacy and highlight the use of neoadjuvant strategies to overcome post-resection immunosuppression in GBM.