**3. Traditional immunotherapy for mRCC**

Cytokine therapy, involving IFN-α and IL-2, was the main treatment for mRCC before the approval of targeted therapies. IFN-α has antiangiogenic effects, promoting antigen presentation and dendritic cell maturation. The efficacy of IFN-α for mRCC patients was first reported in 1989, and it was confirmed that IFN-α is active [11]. The response rate of IFN-α was 15%, with 3–7 months increase in overall survival [12]. However, most responses to IFN-α were not long-lasting and rare patients showed complete responses. In addition, side effects such as flu-like symptoms and liver toxicity disenabled the long-term use of IFN-α. IL-2 is a potent stimulator of T-cell proliferation and differentiation. High dose IL-2 (HD IL-2) was approved in 1992 for treatment of mRCC based on an objective response rate (ORR) between 10 and 20%; many of the responses were durable and continued for a long time [13]. Despite HD IL-2 having become the preferred treatment, there is a limitation of severe toxicity that can prove in various organ systems, most significantly the heart, lungs, kidney, and central nervous system. The treatment of cytokine alone has gradually fallen out of favor from the first-line setting in the current era of targeted therapy and immunotherapy.
