Therapeutic repurposing of old drugs to modulate the tumor immune microenvironment and enhance immunotherapy efficacy.

Although immunotherapy has demonstrated remarkable progress in cancer treatment, its clinical benefits remain restricted to a subset of patients and specific cancer types, primarily due to the immunosuppressive nature of the tumor microenvironment (TME) in solid tumors. Therefore, many strategies have focused on targeting the immunosuppressive TME to enhance immune-mediated tumor eradication. In parallel, the repositioning of old drugs represents an attractive discovery approach compared with the traditional de novo drug discovery process, which is time-consuming and costly. Thus, repurposing US Food and Drug Administration (FDA)-approved old drugs to modulate the tumor immune microenvironment represents a promising strategy to augment the effectiveness of cancer immunotherapy. Indeed, emerging evidence indicates that several approved drugs can reprogram the tumor immune landscape, thereby enhancing responses to immunotherapy. This review provides a comprehensive overview of US FDA-approved old drugs with immunomodulatory properties in the tumor context. We discuss their mechanisms in reversing immunosuppression, summarize key findings from preclinical studies and clinical trials involving their combination with immunotherapies, and outline future perspectives for their clinical translation. Collectively, this work highlights the translational potential of drug repurposing as a strategy to expand the therapeutic reach of cancer immunotherapy.