Oleclumab (MEDI9447; AstraZeneca) is a human IgG1λ monoclonal antibody that binds the catalytic domain of CD73 (encoded by NT5E, ecto-5'-nucleotidase), blocking its enzymatic conversion of extracellular AMP to adenosine and reducing adenosine accumulation in the tumor microenvironment (TME). **HIF-Driven CD73 Induction in SDH-Deficient Tumors:** The mechanistic rationale rests on a direct HIF-1α → NT5E transcriptional axis. Synnestvedt et al. (J Clin Invest 2002, PMID 12370277, DOI 10.1172/JCI15337) established that the NT5E promoter contains a canonical hypoxia-response element (HRE) directly activated by HIF-1α: mutagenesis of this HIF-1 site abolished hypoxia-inducible CD73 expression, and HIF-1α antisense knockdown significantly suppressed hypoxic CD73 upregulation. Samanta et al. (PNAS 2018, PMID 29367423, DOI 10.1073/pnas.1718197115) extended this to cancer cells under hypoxia, showing HIF-1α simultaneously drives CD73, CD47, and PD-L1 — establishing CD73 induction as part of the canonical HIF-1α immunosuppressive transcriptional program. In SDH-deficient tumors, constitutive PHD inhibition by accumulated succinate locks HIF-1α in a permanently active state via the pseudohypoxia pathway (Mechanism 2). This makes NT5E/CD73 transcription constitutive and oxygen-independent — a third, mechanistically distinct immunosuppressive arm operating alongside the succinate-MCT1 axis (Mechanism 11), the HIF-IDO1 axis (Mechanism 11), and the HIF-PD-L1 axis (Mechanism 21). **Downstream Adenosine Immunosuppression:** Tumor-surface CD73 dephosphorylates extracellular AMP to adenosine. Adenosine binds A2A receptors (ADORA2A) and A2B receptors (ADORA2B) on infiltrating CD8+ cytotoxic T cells, CD4+ helper T cells, and NK cells. A2A/A2B receptor activation elevates intracellular cAMP via Gs-coupled adenylyl cyclase → PKA activation → CREB-mediated gene transcription suppressing TCR signaling and effector programs → reduced IFN-γ secretion, degranulation, and cytotoxic T-cell killing. Adenosine simultaneously promotes FoxP3+ regulatory T cell expansion. Leone & Emens (J Immunother Cancer 2018, PMID 29914571, DOI 10.1186/s40425-018-0360-8) reviewed the CD39-CD73-A2A/A2B axis as a major non-checkpoint immune-evasion pathway and highlighted its co-targeting rationale with PD-1/PD-L1 inhibitors. **Combination Rationale:** The adenosine axis is orthogonal to the other immunosuppressive mechanisms in SDH-deficient tumors: it operates via a distinct second-messenger (cAMP) rather than direct metabolite toxicity (succinate-MCT1) or checkpoint ligation (PD-L1/PD-1). This makes oleclumab mechanistically combinable with pembrolizumab/nivolumab (PD-1 blockade, Mechanism 21) without shared target overlap. The NeoCOAST-2 trial (NCT05061550) already tests oleclumab plus durvalumab (anti-PD-L1), providing the clinical scaffold for such combinations. **Clinical Context:** Oleclumab has entered multiple Phase 2 trials in solid tumors: NCT05061550 (NeoCOAST-2; Phase 2, NSCLC, actively recruiting, n=630, oleclumab + durvalumab ± chemotherapy or targeted agents) and NCT03334617 (HUDSON umbrella; Phase 2, NSCLC, active not recruiting, n=528; oleclumab as one of several PD-L1-resistance mechanism arms). These establish Phase 2 dosing, tolerability, and pharmacodynamic data in solid tumor settings. **Key Limitation:** No published data test oleclumab or any CD73 inhibitor in SDH-deficient GIST, PPGL, or RCC models. CD73 protein expression levels in SDH-deficient tumor tissue have not been systematically measured and confirmed. The mechanistic rationale is extrapolated from well-established HIF-1α → NT5E biology in non-SDH-specific hypoxia and cancer models. Direct validation in SDH-null isogenic cell lines (CD73 protein levels, AMP→adenosine conversion rate, oleclumab impact on co-culture T-cell killing assays) is the required next experimental step. Evidence_score 23 (theoretical) reflects a strong three-paper mechanistic chain (PMID 12370277, PMID 29367423, PMID 29914571) but absence of SDH-specific preclinical or clinical data.