Divulging a Pleiotropic Role of Succinate Receptor SUCNR1 in Renal Cell Carcinoma Microenvironment

SIMPLE SUMMARY: Renal cell carcinoma (RCC) is one of the most life-threatening urological neoplasms. The tumor microenvironment comprising immune cell infiltration is a key factor for treatment response and survival of RCC patients. In addition, several studies focused on the involvement of the microbiome in tumor progression via the secretion of metabolic by-products such as succinate. In this study, we have highlighted the potential role of the succinate receptor, SUCNR1, in modulating the tumor microenvironment in the RCC subtypes. Our data displayed a distinct association of SUCNR1 with the microbiome signature, tumor immune infiltrates, and immunomodulators in two different RCC subtypes. This correlation could have potentially contributed to the different survival outcomes of the RCC patients. Thus, SUCNR1 may serve as a promising prognostic factor that might help in improving therapeutic interventions. ABSTRACT: The succinate receptor, SUCNR1, has been attributed to tumor progression, metastasis, and immune response modulation upon its activation via the oncometabolite succinate. Nonetheless, little is known about the prognostic relevance of SUCNR1 and its association with tumor immune infiltrates and microbiota in renal cell carcinoma (RCC). Herein, publicly available platforms including Human Protein Atlas, cBioPortal, TIMER2.0, and TISIDB were utilized to depict a divergent implication of SUCNR1 in the immune microenvironment of clear cell RCC (KIRC) and papillary RCC (KIRP); the two major subtypes of RCC. Our results showed that the SUCNR1 expression level was augmented in RCC compared to other solid cancers, yet with opposite survival rate predictions in RCC subtypes. Consequently, a higher expression level of SUCNR1 was associated with a good disease-specific survival rate (p = 5.797 × 10(−5)) in KIRC patients albeit a poor prognostic prediction in KIRP patients (p = 1.9282 × 10(−3)). Intriguingly, SUCNR1 was mainly correlated to immunomodulators and diverse immune infiltrates in KIRP. Additionally, the SUCNR1 was mostly associated with a repertoire of microbes including beneficial bacteria that likely influenced a better disease-specific survival rate in KIRC. Our findings illustrate a significant novel subtype-specific role of SUCNR1 in RCC which potentially modulates tumor immune infiltration and microbiome signature, hence altering the prognosis of cancer patients.