In summary, through the one‐by‐one analysis of the formation mechanism of drug resistance of PD‐1/PD‐L1 blockers in tumor therapy, it was found that they involved the comprehensive effects of multiple factors including genetics, epigenetics, tumor signaling pathway, cytokines, immunogenicity, antigen presentation, cell metabolism, exosomes, and tumor microenvironment. This evidence concerns the gene CD274 and neoplasm.