This study investigates the molecular and immune cell landscape in melanoma metastases that progress on immune checkpoint blockade (ICB) therapy, focusing on both anti-CTLA4 and anti-PD1 resistance. The authors collected biopsies from 44 patients with melanoma who progressed on either anti-CTLA4 or anti-PD1 monotherapy. They found that genetic alterations in antigen presentation and interferon gamma signaling pathways were observed in approximately 25% of ICB-resistant cases. Anti-CTLA4-resistant lesions showed a sustained immune response, including immune-regulatory features, while anti-PD1-resistant lesions had a distinct immune cell niche but were generally immune-poor with non-expanded T cell receptor (TCR) clones. The study also revealed that anti-PD1-resistant tumors had reduced fractions of PD1+ CD8+ T cells compared to ICB-naïve metastases. Additionally, the authors performed transcriptomic and spatial analyses to explore the differences in immune transcriptional programs and tumor cell states between anti-CTLA4 and anti-PD1 resistant melanomas. They found that anti-CTLA4-resistant tumors had a higher number of expanded TCR clones and an increased abundance of FOXP3+ T regulatory cells, while anti-PD1-resistant tumors had a higher frequency of bystander CD8+ T cells that did not express PD1. These findings highlight the complexity of ICB resistance and the distinct mechanisms underlying resistance to anti-CTLA4 and anti-PD1 therapies.This study investigates the molecular and immune cell landscape in melanoma metastases that progress on immune checkpoint blockade (ICB) therapy, focusing on both anti-CTLA4 and anti-PD1 resistance. The authors collected biopsies from 44 patients with melanoma who progressed on either anti-CTLA4 or anti-PD1 monotherapy. They found that genetic alterations in antigen presentation and interferon gamma signaling pathways were observed in approximately 25% of ICB-resistant cases. Anti-CTLA4-resistant lesions showed a sustained immune response, including immune-regulatory features, while anti-PD1-resistant lesions had a distinct immune cell niche but were generally immune-poor with non-expanded T cell receptor (TCR) clones. The study also revealed that anti-PD1-resistant tumors had reduced fractions of PD1+ CD8+ T cells compared to ICB-naïve metastases. Additionally, the authors performed transcriptomic and spatial analyses to explore the differences in immune transcriptional programs and tumor cell states between anti-CTLA4 and anti-PD1 resistant melanomas. They found that anti-CTLA4-resistant tumors had a higher number of expanded TCR clones and an increased abundance of FOXP3+ T regulatory cells, while anti-PD1-resistant tumors had a higher frequency of bystander CD8+ T cells that did not express PD1. These findings highlight the complexity of ICB resistance and the distinct mechanisms underlying resistance to anti-CTLA4 and anti-PD1 therapies.