JAK2 and cancer: JAK1 and JAK2 are essential signal transducers of the INFγ pathway, therefore, in the setting of AR to ICI, a tumor may become insensitive to INFγ because of loss of JAK1/2.22 Consistently, previous evidence from whole-exome sequencing of four ICI-resistant melanomas revealed acquired loss in JAK1 and JAK2, and preclinical modeling of JAK1 and JAK2 truncating mutations also resulted in cancer cells insensitivity to INFγ, supporting a mechanistic role of these mutations in mediating resistance to ICI.4