BIRC3/CAV1 co-expression drives GBM aggressiveness as a prognostic signature and therapeutic vulnerability.

Glioblastoma (GBM) is an incurable tumor where temozolomide (TMZ) resistance limits survival, even in MGMT-methylated patients. To improve stratification, we used NAD(P)H-FLIM to profile TMZ response in 35 patient-derived explants, integrating these data with transcriptomic and functional analyses. We identified BIRC3 and CAV1 upregulation in resistant tumors and investigated their parallel yet functionally cooperative role in driving an aggressive, therapy-resistant phenotype. In silico survival analyses demonstrated that BIRC3 and CAV1 act as independent prognostic factors whose additive, non-linear effects robustly stratify patient survival beyond MGMT status, defining a subgroup with <7% 24-month survival. Importantly, BIRC3/cIAP2-driven resistance proved targetable; the IAP antagonist AZD5582 restored TMZ sensitivity by unlocking the apoptotic execution phase, thereby inducing cell death in resistant GBM models in vitro and ex vivo. Our findings establish the BIRC3/CAV1 axis as a key prognostic signature and therapeutic vulnerability in GBM, offering a new path for precision oncology strategies.