Yttrium-90 selective internal radiation therapy (Y-90 SIRT; radioembolization) delivers β-radiation to hepatic metastases via hepatic arterial infusion of Y-90-loaded microspheres (SIR-Spheres, SIRTEX; TheraSphere, Boston Scientific). Microspheres lodge in the tumor microvasculature and emit β-radiation (maximum energy 2.27 MeV; mean penetration ~2.5 mm) over ~2 weeks (half-life 64.1 hours), delivering ablative radiation doses (typically 100–300 Gy intratumorally) with relative sparing of surrounding parenchyma. The anatomic rationale for SDH-deficient GIST is direct: unlike KIT/PDGFRA-mutant GIST, SDH-deficient GIST characteristically metastasizes to the liver — not lungs or peritoneum — frequently in young patients where repeated hepatic progression under limited systemic options creates clinical urgency. The molecular rationale for disproportionate radiosensitivity in SDH-deficient GIST flows from the established BRCAness phenotype (Sulkowski et al., Nat Genet 2018, PMID 30013182; Nature 2020, PMID 32494005): SDH loss causes succinate accumulation → α-KG-dependent KDM4A and KDM4B histone demethylase inhibition → H3K9me3 persistence at double-strand break (DSB) sites → impaired TIP60 acetyltransferase and ATM kinase recruitment → defective homologous recombination (HR) repair. HR is the primary pathway for repairing the DSBs generated by ionizing radiation. SDH-deficient cells with BRCAness-driven HR deficiency cannot efficiently repair radiation-induced DSBs, creating selective radiosensitivity relative to HR-proficient surrounding liver parenchyma — an oncometabolite-mediated synthetic vulnerability to radiation. Clinical evidence: Berman et al. (Cancers 2026, PMID 42650014) reported the first dedicated retrospective series of Y-90 SIRT in SDH-deficient GIST across 3 international centers (US, Germany, UK). Among 12 patients with progressive, unresectable hepatic metastases, the objective response rate was 66.7% (1 complete response, 7 partial responses) with 100% disease control rate. Median overall survival was not reached at 32-month follow-up. Only 1 grade ≥3 adverse event was observed. This ORR (66.7%) substantially exceeds that typically reported with Y-90 SIRT in KIT/PDGFRA-mutant GIST or other solid tumor hepatic metastases (ORR typically 20–40%), consistent with the hypothesis of BRCAness-mediated enhanced radiosensitivity rather than a nonspecific hepatic ablation effect. Key limitations: Retrospective design, n=12, no concurrent control arm. The BRCAness mechanism (Sulkowski PMID 30013182, 32494005) is genomically established but has not been directly validated as the causal driver of radiosensitivity in SDH-deficient GIST specifically — it remains a mechanistically grounded hypothesis explaining an observed clinical signal. SIRT is a liver-directed procedure and does not address extrahepatic disease; SDH-deficient GIST without hepatic-dominant pattern would not benefit. Evidence_score 43 reflects direct SDH-deficient GIST-specific clinical data (higher than entries with only indirect mechanistic extrapolation) but not a controlled trial.