Int J Mol Sci. 2026 Nov 2;27(21):9825. doi: 10.3390/ijms27219825.
ABSTRACT
Metastatic clear cell renal cell carcinoma (ccRCC) remains largely incurable, and the efficacy of pembrolizumab plus axitinib may be limited by hypoxia-associated signaling, immunosuppressive cytokines, and metabolic reprogramming involving the TGF-β1/HIF axis. Seleno-L-methionine (SLM) is a pharmacologic inhibitor of this axis and its downstream effectors, including PD-L1 and VEGF. In a phase I/II pilot study (ClinicalTrials.gov NCT05363631), patients with newly diagnosed metastatic ccRCC received SLM twice daily for 14 days, then once daily with standard-dose axitinib; pembrolizumab was added on day 15. Endpoints included circulating (plasma) TGF-β1, plasma selenium, circulating cytokines, efficacy, and safety. Twelve patients were treated and evaluable for safety (six at 5000 µg, six at 6000 µg SLM); ten were evaluable for response. The objective response rate was 70% (complete response 40%, partial response 30%). Of the four patients with CR, two had favorable and two had intermediate International Metastatic Renal Cell Carcinoma Database Consortium disease. Grade 3 hypertension was documented in 58.3%, about twice the pivotal-trial rate, without treatment discontinuations or new toxicities. SLM increased plasma selenium and produced time-dependent inhibition of TGF-β1 and modulation of immune-related cytokines (CXCL13, IFN-γ, TNF-α, IL-6, IL-8). In this pilot study, SLM combined with axitinib and pembrolizumab showed time-dependent TGF-β1 inhibition, cytokine modulation, and encouraging antitumor activity without treatment-limiting toxicity, supporting further investigation of SLM for targeting the TGF-β1/HIF-driven immunosuppressive microenvironment in ccRCC.
PMID:43028071 | DOI:10.3390/ijms27219825
