Historically, it was believed that CD8+ T cells gain effector functions within tumor draining lymph nodes (TDLN), as is seen during viral infections, but recent work in RCC and prostate tumors demonstrates that some CD8+ T cells may undergo a two-phase activation process starting in the TDLN and ending with a second stimulatory signal in the TME [16]. The gene discussed is CD8A; the disease is renal cell carcinoma.