# JAK-STAT signalling

Source: https://onco.cc/pathways/jak-stat/  
OnCo record `jak-stat` (Pathway). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Summary

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.

## Fields

- Kind: Pathway
- Last checked: 2026-09-08
- Tags: mechanism
- Analogy: 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.
- Interventions: 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

- Leading programmes: Levine (MSK) on JAK2 and MPN; Ribas (UCLA) on JAK mutations and PD-1 resistance; Darnell legacy (Rockefeller).

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/JAK-STAT_signaling_pathway
- Hu et al., The JAK/STAT signaling pathway: from bench to clinic (Signal Transduction and Targeted Therapy 2021): https://doi.org/10.1038/s41392-021-00791-1

## Connected records

- cancers: [Chronic myelomonocytic leukaemia and MDS/MPN overlap neoplasms](https://onco.cc/cancers/cmml/), [Cutaneous T-cell lymphoma (mycosis fungoides and Sezary syndrome)](https://onco.cc/cancers/cutaneous-t-cell-lymphoma/), [Hepatosplenic T-cell lymphoma](https://onco.cc/cancers/hepatosplenic-t-cell-lymphoma/), [Hodgkin lymphoma](https://onco.cc/cancers/hodgkin-lymphoma/), [Nodal T-follicular helper cell lymphoma, angioimmunoblastic type (angioimmunoblastic T-cell lymphoma)](https://onco.cc/cancers/angioimmunoblastic-t-cell-lymphoma/), [Non-Hodgkin lymphoma (all types)](https://onco.cc/cancers/non-hodgkin-lymphoma/), [Peripheral T-cell lymphomas (including cutaneous T-cell lymphoma)](https://onco.cc/cancers/peripheral-t-cell-lymphoma/), [Primary mediastinal (thymic) large B-cell lymphoma](https://onco.cc/cancers/primary-mediastinal-b-cell-lymphoma/), [Sezary syndrome](https://onco.cc/cancers/sezary-syndrome/), [T-cell large granular lymphocytic leukaemia](https://onco.cc/cancers/t-large-granular-lymphocytic-leukaemia/)
- targets: [ACVR1 (ALK2)](https://onco.cc/targets/acvr1/), [CIITA](https://onco.cc/targets/ciita/), [JAK1](https://onco.cc/targets/jak1/), [JAK2](https://onco.cc/targets/jak2/), [JAK3](https://onco.cc/targets/jak3/), [MPL (thrombopoietin receptor)](https://onco.cc/targets/mpl/), [PD-L1](https://onco.cc/targets/pdl1/), [SOCS1](https://onco.cc/targets/socs1/), [STAT1](https://onco.cc/targets/stat1/), [STAT3](https://onco.cc/targets/stat3/), [STAT5 (STAT5A, STAT5B)](https://onco.cc/targets/stat5/), [STAT6](https://onco.cc/targets/stat6/)
- institutions: [Mayo Clinic](https://onco.cc/institutions/mayo-clinic/), [Memorial Sloan Kettering Cancer Center](https://onco.cc/institutions/mskcc/)
- pathways: [Antigen presentation & immune editing](https://onco.cc/pathways/antigen-presentation-immunoediting/), [BCR::ABL1 (Philadelphia chromosome)](https://onco.cc/pathways/bcr-abl1-signalling/), [Cancer cachexia](https://onco.cc/pathways/cachexia-biology/), [Chemical carcinogenesis - receptor activation](https://onco.cc/pathways/chemical-carcinogenesis-receptor-activation/), [Fibroblast activation, desmoplasia & matrix stiffness](https://onco.cc/pathways/caf-activation-desmoplasia/), [Inflammation & NF-κB](https://onco.cc/pathways/inflammation-nfkb/), [Myeloid suppression: TAMs, MDSCs & don't-eat-me signals](https://onco.cc/pathways/myeloid-suppression-axis/), [Pancreatic cancer (KEGG map)](https://onco.cc/pathways/pancreatic-cancer-signalling/), [PD-1 / PD-L1 immune checkpoint & T-cell activation](https://onco.cc/pathways/pd1-checkpoint/), [Receptor tyrosine kinase activation](https://onco.cc/pathways/rtk-activation/)
- terms: [Cytokine release syndrome (CRS)](https://onco.cc/terms/crs/), [Enabling characteristic: tumour-promoting inflammation](https://onco.cc/terms/tumor-promoting-inflammation/), [Myeloid-derived suppressor cells (MDSCs)](https://onco.cc/terms/myeloid-derived-suppressor-cells/)
- key papers: [Darnell, Kerr and Stark 1994: JAK-STAT pathways and transcriptional activation by interferons](https://onco.cc/key-papers/paper-darnell-jak-stat-science-1994/), [Grivennikov, Greten and Karin 2010: immunity, inflammation and cancer](https://onco.cc/key-papers/paper-grivennikov-immunity-inflammation-cancer-cell-2010/), [The JAK/STAT signaling pathway: from bench to clinic](https://onco.cc/key-papers/paper-hu-signal-transduct-target-ther/)
- biomarkers: [9p24.1 alteration of the PD-1 ligand loci](https://onco.cc/biomarkers/pd-ligand-9p24-alteration/)
- roadmaps: [Lymphoma roadmap: from a jaw tumour in Uganda and the first human cancer virus to gene-expression subtypes, PET-adapted chemotherapy, CAR-T cells, bispecific antibodies and the genetics-directed trials now recruiting](https://onco.cc/roadmaps/lymphoma-roadmap/)
- ideas: [Treat cachexia before it starts](https://onco.cc/ideas/idea-cachexia-gdf15-prevention/)

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