Through their involvement in cancer metabolism, alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), γ-glutamyltransferase (GGT) and lactate dehydrogenase (LDH) reflect the tumor burden and thus could have a prognostic potential for patients treated with immune checkpoint inhibitors (CPI). Therefore, this study investigated the prognostic potential of these parameters in a real-world cohort of patients with metastatic renal cell cancer (mRCC) under first-line CPI-based therapy. The retrospective study cohort included 82 mRCC patients treated with CPI-based first-line therapy between 2019 and 2023. Progression-free survival (PFS), overall survival (OS) and response rates were evaluated according to baseline levels and early dynamic changes of ALAT, ASAT, GGT and LDH. Multivariate Cox proportional hazard regression models were generated to identify independent prognosticators for PFS and OS. High baseline levels and non-normalized kinetics of ALAT, ASAT, GGT and LDH were significantly associated with shorter PFS and OS (p < 0.05), which was also reflected by lower response rates. Combining the four parameters at baseline into a 4-Risk-Score resulted in an enhanced prognostic power, as indicated by a higher C-index of 0.693 for OS compared to the individual parameters (≤ 0.663). Patients with all four risk factors present showed the worst PFS and OS. Overall, baseline levels and early kinetics of the four parameters as well as the 4-Risk-Score were identified as independent prognosticators for PFS and OS by multivariate analysis. As standard laboratory parameters, ALAT, ASAT, GGT and LDH are cost-effective and could be easily used either alone or in combination for therapy monitoring of CPI-treated mRCC patients.