Stimulator of interferon genes (STING) immunohistochemical expression in fumarate hydratase-deficient renal cell carcinoma: biological and potential predictive implications

Fumarate hydratase (FH)-deficient renal cell carcinoma is an aggressive neoplasm driven by inactivating mutations of the FH gene, which cause metabolites like S-(2-succinyl)cysteine (2SC) to accumulate and trigger cascades supporting malignant transformation. Although in preclinical models the c-GAS-STING pathway is activated by fumarate metabolites, its role in humans has not been explored yet. Eleven FH-deficient renal cell carcinomas, including primary neoplasms and metastases, were retrieved and evaluated for clinical-pathological features and immunohistochemical expression of FH, 2SC (commercially available), and STING. The in-house collection accounted for 0.2% of the 2011-2023 renal cell carcinomas cohort (5/2210). Eight-on-ten cases with available follow-up behaved aggressively (local recurrence/distant metastases). All tumors revealed FH staining loss and strong and diffuse 2SC immunolabeling. At least focal STING expression was detected in most primary tumors (9/11, 82%), often (78%) in a wide percentage of cells (≥ 30%). Notably, significant STING expression was observed in all but two aggressive renal neoplasms, with one of the remaining showing increased staining in its hepatic localization, and in 86% (6/7) of neoplasms significantly expressing PD-L1. In our series, (i) FH-deficient renal cell carcinoma represents 0.2% of in-house cases; (ii) combining FH loss and positive 2SC staining now commercially available is useful in primary and secondary tumors, supporting this latter marker's safe routine adoption; and (iii) a significant STING labeling (≥ 30%) in most of the samples, especially in those behaving aggressively and expressing PD-L1, provides novel insights regarding the molecular basis of FH-deficient renal cell carcinomas, proposing STING as a potential predictive marker.