To synergistically target heterogeneous GBM and the immunosuppressive iTME, we propose the combination of intratumoral (i.t.)CAR T cell therapy and GAM modulation with a T cell-secreted signal regulatory protein gamma (SIRPγ)-related protein (SGRP) for targeting antigen-expressing and bystander tumor cells, yielding a near-complete clearance of EGFRvIII-mosaic GBM in mouse models. This evidence concerns the gene SIRPG and glioblastoma.