Subtype-Specific SASP Dynamics Predict Mesenchymal Transition in Recurrent Glioblastoma

Abstract Background Therapy-induced senescence is hypothesized to promote glioblastoma recurrence through senescence-associated secretory phenotype (SASP) factors, yet no longitudinal study has tracked SASP dynamics across matched primary-recurrent pairs. We used the GLASS consortium to characterize ΔSASP trajectories and their clinical implications. Methods We analyzed 167 matched primary-recurrent GBM pairs from the GLASS consortium. SASP scores were calculated from a 10-gene signature. Patients were classified by ΔSASP trajectory (Accumulators vs Clearers). We tested associations with proneural-to-mesenchymal transition (PMT) and validated findings in TCGA (n=52). Results SASP dynamics were subtype-specific: Mesenchymal tumors showed significant SASP clearance (ΔSASP = −0.83, p = 0.0001), while Classical tumors remained stable (p = 0.86). Among individual genes, HGF was the only factor that increased at recurrence (Δ = +0.23, p = 0.016), while IL1A, IL1B, and MMP9 decreased significantly. ΔSASP strongly predicted mesenchymal transition (OR = 5.06, 95% CI: 2.30-11.18, p < 0.0001), which itself conferred worse survival (HR = 2.48, p = 0.0001). Strikingly, Clearers were nearly completely protected from PMT (2.4% vs 27.3% in Accumulators, p = 0.0008). ΔSASP correlated with immunosuppressive infiltration (ρ = 0.65 with M2 macrophages, p < 0.0001). Baseline SASP predicted worse survival (HR = 1.65, p < 0.0001), an effect that persisted in IDH-wildtype tumors (HR = 1.32, p = 0.015) and was validated in the CGGA cohort (HR = 1.35, p = 0.003). External validation confirmed the SASP-Mesenchymal association in both TCGA (d = 1.75) and CGGA (d = 1.14). Conclusions SASP trajectories are heterogeneous and subtype-specific. Patients who fail to clear SASP represent a high-risk subgroup undergoing mesenchymal transition and immunosuppression. These Accumulators may be optimal candidates for senolytic therapy, while Clearers demonstrate effective senescence surveillance that could be therapeutically reinforced.