The Black Hole of Immune Checkpoint Blocking Therapy for Gastric Cancer: Hyperprogressive Disease

In recent years, immune checkpoint inhibitors (ICIs) represented by PD-1/PD-L1 monoclonal antibodies have shown some good efficacy in various solid tumors such as gastric cancer. However, only about less than 30% of patients benefit from ICIs, and some patients experience rapid tumor growth posttreatment, known as hyperprogressive disease (HPD). Collectively, the overall survival of HPD patients is significantly shorter compared to patients with traditional disease progression, and there is no unified criterion for diagnosing HPD. Some biological mechanisms of HPD in gastric cancer caused by ICIs are still unclear, and factors associated with the occurrence of HPD are uncertain. Notably, it is believed that intrinsic factors, such as abnormal expression of oncogenic genes, and extrinsic factors, including remodeling of the tumor microenvironment, "drift" of immune cell subtypes, may be related to the occurrence of HPD in gastric cancer. Due to its immune stimulatory effects, ICIs may activate certain oncogenic pathways within the tumor, resulting in the appearance of tumor HPD phenomena through increased expression and mutations of some genes, as well as disruption of the balance between immune cells and tumor cells in the tumor microenvironment. Therefore, this review summarizes the mechanisms, predictive biomarkers, prevention, and treatment methods of HPD after immune checkpoint blockade therapy, providing a theoretical basis for making a judgment on the efficacy of ICI treatment for gastric cancer.