Abstract: Immune checkpoint inhibitors (ICIs) have become an important therapeutic approach for various malignant tumors; however, their efficacy varies among individuals and is associated with the risk of immune-related adverse events. The gut microbiota, as a key exogenous factor regulating host immune homeostasis and antitumor immune responses, plays an important regulatory role in immunotherapy outcomes. Proton pump inhibitors (PPIs), commonly used acid-suppressive medications in patients with cancer, may influence the efficacy and safety of ICIs by disrupting the intestinal microecology. This review summarizes the research progress on the regulation of ICI efficacy and safety by PPIs via gut microbiota, and reviews relevant clinical evidence and potential biological mechanisms. A synthesis of current studies suggests that PPIs may impair the gastrointestinal microbial ecological barrier by suppressing gastric acid secretion, promote the translocation of oral-derived microbiota into the intestine, reduce short-chain fatty acid-producing bacteria and beneficial commensal bacteria, promote the expansion of opportunistic pathogens, and increase intestinal permeability. These alterations may subsequently affect antigen presentation by dendritic cells, cytotoxic T-cell activation, and the tumor immune microenvironment, thereby reducing the antitumor efficacy of ICIs and increasing the risk of certain immune-related adverse events. This review provides a scientific basis for the rational clinical use of acid-suppressive medications, enhancement of immunotherapy efficacy, and implementation of individualized cancer interventions.