Meta-analyses reveal that antibiotics and proton pump inhibitors significantly worsen outcomes in cancer patients receiving immune checkpoint inhibitors, establishing a new category of drug interactions that operate through immunological rather than metabolic mechanisms. These "immunological DDIs" work by disrupting the gut microbiome, suppressing systemic immunity, and altering the tumor microenvironment—pathways critical for anti-cancer immune responses. This represents a paradigm shift in understanding drug interactions beyond traditional pharmacokinetic models. The implications extend far beyond oncology, as millions take proton pump inhibitors for acid reflux and receive antibiotics routinely. For cancer patients, timing medication around immunotherapy could be crucial for treatment success. However, the observational nature of current evidence means causation remains uncertain—sicker patients naturally receive more medications, creating confounding. The integration of AI approaches to parse complex real-world data offers promise for identifying these subtle but clinically meaningful interactions. This work establishes immunological drug interactions as a legitimate research field, potentially affecting how we approach polypharmacy in an aging population where immune function becomes increasingly vital for health outcomes.