SLC-0111 (WBI-5111; Welichem Biotech) is an orally bioavailable, selective small-molecule inhibitor of the transmembrane carbonic anhydrase isoforms CA9 (CAIX) and CA12 (CAXII), with >100-fold selectivity over the cytosolic CA1 and CA2 isoforms. CA9 catalyses the extracellular hydration of CO₂ to H⁺ + HCO₃⁻, acidifying the tumour microenvironment; CA12 has a similar orientation but is expressed in different tissue contexts. By inhibiting the transmembrane isoforms selectively, SLC-0111 restores extracellular pH homeostasis without disrupting essential cytosolic carbonic anhydrase functions in erythrocytes, kidney, and stomach. **SDH-specific mechanistic chain:** SDH loss → succinate accumulation → competitive inhibition of PHD2/PHD3 prolyl hydroxylases → constitutive stabilisation of HIF-1α and HIF-2α → HIF-α/HIF-1β heterodimer binds the HIF-1-dependent hypoxia-response element (HRE) in the CA9 minimal promoter → constitutive CA9 transcription and membrane-localised CA9 expression. Wykoff et al. (Cancer Res 2000, PMID 11156414) established this HIF→CA9 regulatory axis: in VHL-deficient renal carcinoma cells (constitutive HIF because pVHL cannot degrade PHD-unhydroxylated HIF-1α), CA9 is constitutively expressed independent of oxygen, and this regulation is recapitulated by constitutive HIF-1α stabilisation in other cell types. SDH-deficient tumours share the same PHD-inhibition mechanism but initiated by succinate rather than VHL loss, making CA9 constitutively expressed in SDH-deficient GIST, PPGL, RCC, and pituitary adenoma — exactly as observed for VHL-related tumours. **Functional consequences of CA9-mediated tumour acidosis:** Constitutive CA9 activity generates an extracellular acid load (pHe ~6.5–6.9 in pseudohypoxic tumour cores) against a near-neutral intracellular pH (~7.2). This reverse pH gradient: 1. Activates acid-dependent proteases (cathepsins B, D, L; MMP-2, MMP-9) at the cell surface → invasion and basement membrane degradation 2. Suppresses CD8⁺ T-cell cytolytic function and NK-cell activity (lactic acid + H⁺ inhibit TCR signalling at ~pH 6.5) → immune evasion in the TME 3. Traps weakly basic chemotherapeutic drugs (doxorubicin, vinca alkaloids, paclitaxel) in the protonated, membrane-impermeant form in the extracellular space → reduced intracellular drug accumulation → multidrug resistance SLC-0111 inhibition reverses extracellular acidification, restoring each of these pH-dependent vulnerabilities. **CAIX expression in SDH-deficient/pseudohypoxic PPGL:** Mete et al. (Am J Surg Pathol 2021, PMID 33826547) confirmed CAIX membranous staining in pseudohypoxic cluster 1 PPGLs (SDHx and VHL-related), with NF1- and RET-driven cluster 2 PPGLs being CAIX-negative. CAIX is noted as the most specific (though not most sensitive) IHC biomarker of VHL-related PPGL in their cohort; SDHx-related cases with pseudohypoxia showed CAIX staining consistent with HIF-driven CA9 transcription. **Clinical data:** - NCT02215850 (Phase 1 monotherapy; Welichem Biotech; 24 patients with advanced solid tumours; COMPLETED): established safety, tolerability, and PK of oral SLC-0111 in humans. - NCT03450018 (Phase 1b/2 combination with gemcitabine; BC Cancer; CAIX-positive metastatic pancreatic ductal adenocarcinoma; TERMINATED at n=6): terminated due to slow enrolment (CAIX-positive IHC selection reduced the eligible pool) rather than toxicity. **Key limitations:** 1. CAIX IHC sensitivity in SDH-deficient tumours: Mete et al. 2021 showed only 16% membranous CAIX staining overall across all PPGLs tested; most CAIX-positive cases were VHL-related rather than SDHx-related. Constitutive pseudohypoxia driven by succinate may not universally achieve the HIF-1α transcriptional threshold required for IHC-detectable CA9 in all SDH-deficient tumour types. 2. No published preclinical data testing SLC-0111 specifically in SDH-null cell lines or xenografts; the SDH-specific rationale is mechanistic extrapolation from the HIF→CA9 pathway (PMID 11156414) and PPGL CAIX staining data (PMID 33826547). 3. pH-targeting as monotherapy may have limited efficacy; combination with immunotherapy (to restore immune TME pH) or chemotherapy (to restore intracellular drug accumulation) may be required. Evidence_score 20 (theoretical): strong HIF-driven mechanistic chain (PMID 11156414) + CAIX expression in pseudohypoxic PPGLs (PMID 33826547) + Phase 1 clinical safety data (NCT02215850); held at 20 because of weak CAIX IHC sensitivity in SDHx PPGLs specifically, absence of SDH-deficient preclinical models, and the terminated combination trial.