Our results show that increased high pretreatment sucralose intake was associated with lower PFS in patients with advanced cutaneous melanoma and NSCLC treated with PD-1–based ICI regimens, and lower RFS in patients with high-risk resectable melanoma treated with anti–PD-1 and TLR9 agonist, hinting at the ability of sucralose to blunt the efficacy of ICI immunotherapy regardless of histology or stage. Here, TLR9 is linked to non-small cell lung carcinoma.