With rejuvenated preclinical and clinical development of novel IL-2 variants via biochemical modifications and cytokine engineering and promising clinical data suggesting improved single-agent activity for newer agents such as nemvaleukin alfa in solid tumor malignancies beyond the established FDA indications of metastatic melanoma and renal cell carcinoma, certain IL-2 variants are poised to serve as viable platforms for combination with anti-PD-(L)1 and anti-CTLA-4 immunotherapy, chemotherapies, and targeted therapy approaches. This evidence concerns the gene CD274 and hereditary clear cell renal cell carcinoma.