JAK–STAT signalling
The relay that turns cytokine signals into gene changes. Overactive in blood cancers (JAK2 in myelofibrosis), it is also the wire that carries interferon's cancer-killing message, so tumours cut it to escape immunotherapy.
Cytokine receptors recruit JAK kinases that phosphorylate STAT transcription factors. JAK2 V617F drives myeloproliferative neoplasms (ruxolitinib, fedratinib, momelotinib approved); STAT3 is a hub for IL-6-driven survival, immunosuppression, and cachexia; STAT5 in leukaemias. Interferon-γ signalling via JAK1/2–STAT1 upregulates MHC and PD-L1; JAK1/2 loss-of-function mutations cause acquired resistance to PD-1 blockade. Direct STAT3 inhibitors (degraders, antisense) are in early trials.
In one picture
JAK–STAT is a doorbell wired to the house lights. Cytokines ring, JAK flips the switch, STAT turns on the lights. Cancers either jam the switch on (JAK2 mutation) or cut the wire so interferon cannot turn on the 'I am infected' lights.
Diagram
top- JAK inhibitors in myeloproliferative neoplasms and GVHD
- STAT3 degraders/antisense (early trials)
- Anti-IL-6 (tocilizumab) for CRS and under study for cachexia
- JAK-loss tumours: MHC-independent therapies (T-cell engagers, NK cells)
Notes
top- Leading programmes: Levine (MSK) on JAK2 and MPN; Ribas (UCLA) on JAK mutations and PD-1 resistance; Darnell legacy (Rockefeller).