BACKGROUND: Immunotherapies targeting PD-1 and CTLA-4 are key components of the treatment of metastatic clear cell renal cell carcinoma (mccRCC). However, they have distinct safety profiles and resistance to treatment can occur. We assess soluble TIM-3 (sTIM-3) in the plasma of mccRCC patients as a potential theranostic biomarker, as well as its source and biological significance. METHODS: We analyzed the association between sTIM-3 and overall survival (OS), tumor response, and common clinical and biological factors in two mccRCC cohorts treated with anti-PD-1 (nivolumab, n = 27), anti-PD-1 or anti-PD-1 + anti-CTLA-4 (nivolumab + ipilimumab - N + I, n = 124). The origin and role of sTIM-3 are studied on tumor and blood samples, using multiplex immunohistochemistry and flow cytometry, as well as analyses of publicly available single-cell transcriptomic (scRNAseq) and mass cytometry data. RESULTS: sTIM-3 is significantly elevated in the plasma of treatment-naive mccRCC. It shows distinct associations with survival on anti-PD-1 vs anti-PD-1 + anti-CTLA-4: under nivolumab monotherapy, sTIM-3-high patients have a significantly reduced survival compared to sTIM-3-low patients, while they have similar survival probabilities under N + I. sTIM-3 is independent from other clinical and biological factors. Myeloid immune cells appear as the prominent source of sTIM-3, which may indicate their dysfunctional role in the antitumor immune response. CONCLUSIONS: sTIM-3 appears to be a promising biomarker for optimizing treatment strategies in ccRCC as well as a potential therapeutic target, linked with to the immune myeloid compartment. Future investigations are warranted in patients treated with anti-PD-1 + antiangiogenic therapies.