This study explores the use of synNotch-programmed induced pluripotent stem cell (iPSC)-derived natural killer (NK) cells to target the TIGIT-CD155 and CD73 axes in glioblastoma (GBM). The TIGIT-CD155 axis is a key immunosuppressive pathway in GBM, while CD73 contributes to immunosuppression by producing adenosine. The study demonstrates that engineered synNotch-based NK cells can usurp TIGIT and CD73 activities, leading to the localized blockade of CD73 and disruption of immunosuppressive adenosine production. This approach enhances NK cell function and promotes tumor eradication in GBM models. The synNotch system allows for the activation of NK cells upon binding to CD155, which triggers the release of an anti-CD73 scFv, thereby blocking CD73 activity and promoting NK cell cytotoxicity. The engineered NK cells also reprogram the GBM microenvironment by recruiting T cells and reducing M2 macrophages, leading to improved anti-tumor responses. The study shows that synNotch-engineered iPSC-derived NK cells are effective in targeting both TIGIT-CD155 and CD73, offering a promising allogeneic therapy for GBM. The results highlight the potential of dual-targeting strategies in overcoming the immunosuppressive environment of GBM and improving therapeutic outcomes. The study also addresses the challenges of NK cell dysfunction in GBM, demonstrating that engineered NK cells can overcome these limitations and provide effective, targeted therapy. The findings suggest that targeting TIGIT-CD155 and CD73 axes could be a valuable approach for GBM treatment, with potential for clinical translation.This study explores the use of synNotch-programmed induced pluripotent stem cell (iPSC)-derived natural killer (NK) cells to target the TIGIT-CD155 and CD73 axes in glioblastoma (GBM). The TIGIT-CD155 axis is a key immunosuppressive pathway in GBM, while CD73 contributes to immunosuppression by producing adenosine. The study demonstrates that engineered synNotch-based NK cells can usurp TIGIT and CD73 activities, leading to the localized blockade of CD73 and disruption of immunosuppressive adenosine production. This approach enhances NK cell function and promotes tumor eradication in GBM models. The synNotch system allows for the activation of NK cells upon binding to CD155, which triggers the release of an anti-CD73 scFv, thereby blocking CD73 activity and promoting NK cell cytotoxicity. The engineered NK cells also reprogram the GBM microenvironment by recruiting T cells and reducing M2 macrophages, leading to improved anti-tumor responses. The study shows that synNotch-engineered iPSC-derived NK cells are effective in targeting both TIGIT-CD155 and CD73, offering a promising allogeneic therapy for GBM. The results highlight the potential of dual-targeting strategies in overcoming the immunosuppressive environment of GBM and improving therapeutic outcomes. The study also addresses the challenges of NK cell dysfunction in GBM, demonstrating that engineered NK cells can overcome these limitations and provide effective, targeted therapy. The findings suggest that targeting TIGIT-CD155 and CD73 axes could be a valuable approach for GBM treatment, with potential for clinical translation.