There are few studies directly linking NOTCH signaling with ICB therapy in addition to Donghai Xiong’s finding that in one patient with esophageal squamous cell carcinoma (ESCC) who developed HPD after anti-PD-1 immunotherapy, somatic mutations of NOTCH4 were not present in the pretherapy tumor (61). Here, NOTCH4 is linked to esophageal squamous cell carcinoma.