Background: Anti-Programmed Cell Death-1 (PD-1) antibodies have considerably changed the treatment for melanoma. However, many patients do not display therapeutic response or eventually relapse. Moreover, patients treated with anti-PD-1 develop immune-related adverse events that can be cured with anti-Tumor Necrosis Factor α (TNF) antibodies. Whether anti-TNF antibodies affect the anti-cancer immune response remains unknown. Our recent work has highlighted that TNFR1-dependent TNFα signaling impairs the accumulation of CD8+ tumor-infiltrating T lymphocytes (CD8+ TIL) in mouse melanoma (Bertrand et al., Cancer Res. 2015). Our unpublished data indicate that in mice TNF or TNFR1 blockade synergizes with anti-PD-1 on anti-cancer immune response towards solid cancers. Mechanistically, TNF blockade prevents anti-PD-1-induced TIL cell death as well as PD-L1 and TIM-3 expression. TNF expression positively correlates with expression of PD-L1 and TIM-3 in human melanoma specimens (Bertrand, Montfort et al., Nat. Commun., in press). This study provides a strong rationale to develop a combination therapy based on the use of anti-PD-1 and anti-TNF in cancer patients. An ongoing phase 1b clinical trial (NCT03293784) will evaluate the safety and tolerance of the combination of immune checkpoint inhibitors and anti-TNF in metastatic melanoma patients in our institute (Institut Universitaire du Cancer, Toulouse).