Clear Cell Renal Cell Carcinoma

After prior ICI exposure, VEGFR-TKIs continue to represent the treatment backbone, while later-line options such as hypoxia-inducible factor-2α (HIF-2α) inhibitors and lenvatinib-everolimus further expand sequencing possibilities. Randomized studies have not shown consistent benefit for routine ICI rechallenge in unselected populations. Overall, advanced ccRCC management requires structured individualization, while validated predictive biomarkers and prospective sequencing data remain important unmet needs.

The UPR-CEBPB-MIF signaling axis is associated with macrophage polarization and an immunosuppressive immune microenvironment in ccRCC. The proposed multi-omics model demonstrates stable prognostic value and provides potential targets for optimizing immunotherapy.

CALYPSO (NCT02819596) was a prospective, multi-arm trial that evaluated durvalumab alone or in combination with tremelimumab or savolitinib in metastatic ccRCC and pRCC. Also, an increase in KIM-1 during therapy was linked to worse progression-free survival (HR 1.7; 95% CI, 1.13-2.58; p = 0.01) and OS (HR 1.95; 95% CI, 1.23-3.08; p = 0.004) in ccRCC. This exploratory analysis supports the utility of KIM-1 in advanced ccRCC and pRCC.

P1, N=30, Suspended, City of Hope Medical Center | Trial completion date: Mar 2026 --> Jun 2026 | Trial primary completion date: Mar 2026 --> Jun 2026

Importantly, treatment with Eeyarestatin I, a small-molecule ER stress agonist, restored sunitinib sensitivity in tumor cells. These findings reveal a novel PABPC1-PGK1 regulatory axis underlying sunitinib resistance and suggest a promising therapeutic strategy for overcoming drug resistance in ccRCC.

Spatial patterns of immune and vascular components at the tumor-stroma interface independently predict PFS in patients with ccRCC following nephrectomy and may improve current risk stratification schemes in both the immediate postoperative setting and during follow-up.

P2, N=18, Not yet recruiting, Mayo Clinic

In this review, we explore the unconventional tumor-suppressive function of YAP/TAZ and the mechanisms through which they inhibit tumor growth, with an emphasis on recent findings in hormone-regulated cancers and ccRCC. Finally, we discuss the therapeutic implications of these emerging findings for cancer treatment.

P2, N=46, Active, not recruiting, Brown University | Trial completion date: Mar 2026 --> Sep 2026 | Trial primary completion date: Jan 2026 --> Jun 2026

Strikingly, VHL-deficient ccRCC exhibits greater on-target pathway sensitivity to dexamethasone at the H4K12la-glycolysis axis, and glucocorticoid dexamethasone potentiated the antitumor efficacy of the HIF-2α inhibitor belzutifan in both orthotopic cell line-derived and patient-derived xenograft models. Collectively, our findings establish H4K12la as a metabolic‒epigenetic amplifier in VHL-deficient ccRCC, reposition glucocorticoids as epigenetically active modulators that dampen lactate-driven chromatin activation and glycolytic output, and provide a mechanistically grounded combination strategy with HIF-2α blockade to target lactate-fueled transcriptional dependence in metabolically rigid tumors.

P1, N=70, Recruiting, Compass Therapeutics | Not yet recruiting --> Recruiting

P3, N=40, Recruiting, Telix Pharmaceuticals (Innovations) Pty Limited | Not yet recruiting --> Recruiting | Initiation date: Nov 2025 --> Mar 2026 | Trial primary completion date: Dec 2026 --> Aug 2027