JAK1/JAK2 Loss and Interferon-Signalling Resistance to Immunotherapy

The Interferon-Gamma Circuit

Interferon gamma binds its receptor on the tumour cell, activating the receptor-associated kinases JAK1 and JAK2, which phosphorylate STAT1. STAT1 then drives transcription of hundreds of genes, including those for MHC class I and II, the antigen-processing machinery, and PD-L1.

Loss of JAK1 or JAK2 breaks this circuit. The tumour cell can no longer be forced to display more antigen or to arrest in response to a T-cell attack.

Primary and Acquired Resistance

Homozygous JAK1 or JAK2 loss-of-function mutations were identified in melanomas that relapsed after an initial response to PD-1 blockade, with the mutant clone expanding under treatment. JAK pathway defects are also found in tumours that never respond, a form of primary resistance.

Because interferon signalling also induces PD-L1, a JAK-deficient tumour may show low PD-L1 despite being T-cell infiltrated, which can mislead biomarker interpretation.

A Double-Edged Pathway

Interferon signalling is mostly anti-tumour, but chronic low-level interferon exposure can also upregulate inhibitory ligands and promote resistance, so the pathway is not uniformly beneficial.

There is no approved way to restore interferon responsiveness in a JAK-deficient tumour, and JAK mutation testing is not yet a standard predictive assay.

Reading It Alongside a PD-L1 Result

The practical trap is biomarker misinterpretation. A JAK1- or JAK2-deficient tumour cannot upregulate PD-L1 in response to interferon, so it can score PD-L1-low even when heavily T-cell infiltrated. A PD-L1-low result in an otherwise inflamed tumour, or an unexpected non-response, is a reason to look for an antigen-presentation or interferon-pathway defect on sequencing.

There is no treatment that repairs the pathway, so management centres on choosing therapies that do not rely on tumour interferon responses — such as T-cell-redirecting bispecifics or, in the right disease, CAR T cells — and on recognising that combination immunotherapy is unlikely to overcome a hard genetic loss.

Key Takeaways

• ·JAK1 and JAK2 transmit interferon-gamma signals that boost tumour antigen presentation.
• ·Loss-of-function JAK mutations cause both primary and acquired checkpoint-inhibitor resistance.
• ·JAK deficiency can produce low PD-L1 staining despite T-cell infiltration, complicating biomarker use.