A longitudinal study of 175 patients with advanced melanoma undergoing immune checkpoint blockade (ICB) reveals distinct gut microbiome changes associated with progression-free survival (PFS) of ≥12 months versus <12 months. Using shotgun metagenomics and MetaPhlAn4, researchers identified 99 species-level genome bins (SGBs) that could distinguish between these groups. Twenty SGBs showed differential abundance only at baseline, while 42 were differentially abundant after treatment initiation. Five SGBs were consistently higher in patients with PFS ≥12 months, and four were consistently higher in those with PFS <12 months. A log ratio of these SGBs was associated with overall survival. The study also found different microbial dynamics in various clinical contexts, including ICB regimen, development of immune-related adverse events (irAEs), and concomitant medication use. The gut microbiome's longitudinal changes, influenced by host factors and treatment regimens, are critical for guiding microbiome-targeted therapies to enhance ICB efficacy. The study highlights the importance of longitudinal microbiome profiling to understand how microbial changes correlate with treatment outcomes and adverse events. It also shows that baseline microbial profiles may not predict long-term outcomes, as microbial dynamics can vary significantly during treatment. The findings suggest that microbiome-targeted interventions should consider the dynamic nature of the gut microbiome and its interactions with host factors and treatment regimens. The study underscores the need for further research to develop more effective microbiome-based therapies for ICB.A longitudinal study of 175 patients with advanced melanoma undergoing immune checkpoint blockade (ICB) reveals distinct gut microbiome changes associated with progression-free survival (PFS) of ≥12 months versus <12 months. Using shotgun metagenomics and MetaPhlAn4, researchers identified 99 species-level genome bins (SGBs) that could distinguish between these groups. Twenty SGBs showed differential abundance only at baseline, while 42 were differentially abundant after treatment initiation. Five SGBs were consistently higher in patients with PFS ≥12 months, and four were consistently higher in those with PFS <12 months. A log ratio of these SGBs was associated with overall survival. The study also found different microbial dynamics in various clinical contexts, including ICB regimen, development of immune-related adverse events (irAEs), and concomitant medication use. The gut microbiome's longitudinal changes, influenced by host factors and treatment regimens, are critical for guiding microbiome-targeted therapies to enhance ICB efficacy. The study highlights the importance of longitudinal microbiome profiling to understand how microbial changes correlate with treatment outcomes and adverse events. It also shows that baseline microbial profiles may not predict long-term outcomes, as microbial dynamics can vary significantly during treatment. The findings suggest that microbiome-targeted interventions should consider the dynamic nature of the gut microbiome and its interactions with host factors and treatment regimens. The study underscores the need for further research to develop more effective microbiome-based therapies for ICB.