Renal cell carcinoma (RCC) is a common malignant tumor of the urinary system, accounting for approximately 80% of urinary tract malignancies, with clear cell renal cell carcinoma (ccRCC) being the most prevalent subtype. Despite its high incidence, the pathogenesis of ccRCC remains incompletely elucidated, and limitations persist in early diagnosis, targeted therapy, and immunotherapy. Based on emerging evidence highlighting the critical role of liquid-liquid phase separation (LLPS) in tumor proliferation and invasion, this study leveraged multiple ccRCC cohorts to employ Mendelian randomization (MR) and ultimately developed a novel Bidirectional Liquid-Liquid Phase Separation-associated Index (B-LLPSI) using LASSO regression, aiming to predict patient prognosis and therapeutic response. Notably, B-LLPSI demonstrates substantial potential as a universal prognostic indicator across multiple cancer types, underpinning its prospective application in individualized oncology. Paradoxically, while high B-LLPSI levels correlate with poorer patient prognosis, they simultaneously predict enhanced responsiveness to immunotherapy. Furthermore, the B-LLPSI signature was found to be upregulated in tumor tissues and capable of promoting tumor proliferation and invasion. In summary, B-LLPSI holds promise as a robust and independent prognostic tool for diverse cancers, providing critical insights for formulating individualized treatment strategies.