Background: Immune checkpoint blockade improves the survival of patients with metastatic melanoma, but many patients fail to respond to immunotherapy and the lack of accurate predictors of response or progression remains a major clinical problem. We investigated potential mechanisms of response and resistance to anti-PD1 +/- ipilimumab. Methods: 141 melanoma biopsies from advanced melanoma pts treated with anti-PD-1 monotherapy (n= 54), or anti-PD1 + ipilimumab (n= 51) were classified as responders (CR/PR/SD > 6 mo) or non-responders (SD≤6 mo/PD) based on RECIST. The transcriptomic and immunophenotypic profiles of 105 baseline (PRE) and 36 early-during treatment (EDT) tumor biopsies from pts treated with monotherapy (n= 33 responders, n= 21 non-responders) or anti-PD-1 + ipilimumab (n= 38 responders, n= 13 non-responders) were characterized via RNA sequencing and multiplex immunofluorescence. Results: Responders to monotherapy displayed increased expression of genes associated with a Type 1 interferon response, tissue-resident T-cells and drug targets (TIGIT, ADAR, ADORA2A, CD137, IDO1 and LAG3) (diff. p < 0.05). Genes unique to anti-PD-1 + ipilimumab responders included T-cell and NK-cell genes EOMES, CD48, CD96, and FASLG. Non-responders displayed significantly higher expression of genes associated with WNT signaling along with novel hypoxic and metabolic pathways, including CA9 and NABP1 (p < 0.05). Non-responders with high CD8/PD-L1 densities expressed novel immune drug targets (IDO1 expressed by 37% of monotherapy non-responders, ICOS (37%), TNFRSF9 (26%), LAG3 (16%), TIGIT (16%) and ADORA2A (16%)). In contrast, TIL-low tumors displayed a lack of expression of the aforementioned targets (42% of monotherapy and 86% of anti-PD-1 + ipilimumab non-responders). Conclusions: These findings demonstrate that combinations of novel drug targets may provide clinical benefits in non-responding and non-CR responding patients with high TILs. TIL-low non-responders may require modulation of WNT, hypoxic and metabolic pathways to overcome resistance, facilitating the development of novel synergistic drug targets.