Immunotherapy has recently emerged as a promising treatment option for many patients, revolutionizing the established therapeutic approach against cancer. Immune checkpoints inhibitors (ICIs) have demonstrated clinical activity in a wide spectrum of malignancies; however, only a minority of patients exhibit durable responses. This response heterogeneity may be partly attributed to host related factors, such as body mass index (BMI), diet and gut microbiome, that have recently emerged as strong influences in ICI responsiveness. Obesity not only directly impacts on cancer promotion but also on the immune homeostasis and the elimination, equilibrium, and escape phases of immune-editing. Paradoxically, emerging clinical data indicate that obese patients are benefited from ICI therapy when compared to normal BMI cancer patients. Interestingly, strong evidence supports the role of the microbiome in cancer immunotherapy, with several recent animal, translational/hybrid and clinical studies demonstrating its influence in the response to ICIs across several malignancies. Noteworthy, nutrition, through its well-established links to obesity, microbiome composition and oncogenicity, may contribute towards leveraging its effects in favor of cancer patients alongside with gold standard treatments. The aim of this review is to delineate the associations of ICIs with obesity, host microbiome and nutrition, and to explore how these factors can be effectively leveraged in enhancing the effectiveness of immunotherapy. More specific aims include the determination of how patients with obesity are differentially affected by ICI therapy; how the host microbiome affects response to ICIs; and how the microbiome itself is modulated by obesity and nutrition. In conclusion, immunometabolism, microbiome and nutrition research present the potential to offer unique tools in unleashing ICIs full potential; providing host-derived, actionable, modifiable targets directly associated with therapeutic outcomes that can be efficiently leveraged. Future efforts, provided that they adhere to robustness of methodology, can facilitate transferring these findings, from bench to bedside.