As longer-term clinical and real-world data accumulate, including 10-year follow-up with nivolumab plus ipilimumab in advanced melanoma and landmark safety analyses with pembrolizumab (10, 11), it is increasingly clear that, despite their transformative role, PD-1/PD-L1 antibodies deliver durable benefit only for a subset of patients and are constrained by immune-related toxicities, organ-specific barriers, and the practical burden of prolonged intravenous treatment. The gene discussed is PDCD1; the disease is melanoma.