Immune checkpoint inhibitors (ICIs) have transformed the treatment of multiple malignancies, yet durable clinical responses remain limited to a subset of patients. Accumulating evidence identifies the gut microbiome as a regulator of antitumour immunity that can influence treatment efficacy and toxicity through microbial metabolism, epithelial barrier integrity, inflammatory signalling, and host immune responses. This review critically evaluates the microbiome as both a predictive biomarker and therapeutic target in precision oncology. It moves beyond descriptive taxonomic associations by assessing emerging functional and mechanistic models that integrate microbial metabolites, ecological interactions, strain-level variation, and host–microbiome communication. Clinical and translational evidence from melanoma, non-small cell lung cancer, colorectal cancer, hepatocellular carcinoma, renal cell carcinoma, and urothelial carcinoma reveals marked differences in the reproducibility and clinical maturity of reported microbial signatures. Emerging microbiome-targeted strategies, including dietary modulation, faecal microbiota transplantation (FMT), live biotherapeutic products (LBPs), and defined microbial consortia, may enhance ICI responsiveness, with responder-derived FMT providing important early clinical proof of concept. However, inter-individual variability, donor–recipient compatibility, microbial engraftment, the lack of standardised analytical approaches, and unresolved safety and regulatory requirements continue to limit clinical translation. Pending prospective validation, reasonable clinical practice is to avoid unnecessary microbiome-disrupting antibiotics, systematically document diet and concomitant medications, evaluate FMT and LBPs within regulated clinical trials, and interpret microbiome profiles alongside established tumour and host biomarkers rather than as stand-alone tests. Current evidence therefore supports a cautious shift towards functional microbiome-guided precision oncology, providing a foundation for personalised strategies to improve cancer immunotherapy outcomes.