Oral alkylating prodrug that hydrolyzes spontaneously to MTIC, which methylates DNA at guanine N7 and O6 positions. O6-methylguanine adducts are normally excised by MGMT (O6-methylguanine-DNA methyltransferase); when MGMT is silenced, unrepaired O6-methylguanine pairs with thymine during replication, triggering mismatch-repair-mediated apoptosis. In SDH-deficient tumors, succinate accumulation competitively inhibits TET methylcytosine dioxygenases (α-KG-dependent) causing genome-wide CpG hypermethylation — the CpG Island Methylator Phenotype (CIMP) documented in SDH-deficient GIST (Killian et al., Cancer Discov 2013, PMID 23550148) and in SDH-deficient PPGL (Letouzé et al., Cancer Cell 2013, PMID 23707781). The MGMT promoter CpG island is a direct CIMP target in these tumors, making MGMT silencing a predictable downstream consequence of SDH loss and creating intrinsic TMZ sensitivity. In a prospective study of 62 metastatic PPGL patients, TMZ monotherapy achieved 83% disease control rate, 24% overall response rate, and median PFS 25.2 months; MGMT promoter methylation >7% predicted 92.9% disease control rate versus undetectable response in MGMT-unmethylated controls (Cui et al., J Endocrinol Invest 2024, PMID 38837102). SDHB-mutant patients were represented in this cohort, consistent with the SDH-CIMP-MGMT mechanistic axis.