Immune therapy-related hyperprogressive disease: Molecular mechanisms, biomarkers, and clinical strategies

Programmed death receptor-1 inhibitors have significantly improved the prognosis of various malignancies. Nevertheless, hyperprogressive disease (HPD), recognized as a severe adverse reaction to immunotherapy, causes a substantial surge in tumor burden and notably shortens the survival of 4%-29% of patients. This article comprehensively reviews the controversies regarding the clinical definition of HPD, its cross-cancer epidemiological features (encompassing gastric cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, <i>etc.</i>), and potential molecular mechanisms (such as <i>MDM2</i>/<i>MDM4</i> gene amplification, <i>EGFR</i> mutations, and reprogramming of the immune microenvironment). It further delves into biomarker-based predictive models, targeted combination therapy strategies, and salvage treatment alternatives. Ultimately, it puts forward future directions, including the establishment of a multicenter HPD registry database and organoid predictive models, aiming to offer evidence-based guidance for clinical practice.