Australian researchers have discovered that the TAK1 gene helps cancer cells survive attack from the immune system, revealing a mechanism that may limit the effectiveness of immunotherapy treatments.
Cancer immunotherapies can work very well, but underperform in some cases due to tumours’ inbuilt survival processes that help them resist attack by the immune system.
Researchers at the Olivia Newton-John Cancer Research Institute (ONJCRI) and WEHI discovered that the TAK1 gene acts like a safety switch that protects cancer cells from the powerful signals generated by CD8⁺ T cells.
TAK1 was identified by conducting a large genetic screen to search for genes that help cancer cells survive attacks by CD8⁺ T cells, key killer cells of our immune system.
Dr Anne Huber, Postdoctoral Researcher at ONJCRI, affiliated with La Trobe University as the School of Cancer Medicine, says:
“It is known that TAK1 promotes cancer cell survival and blocks cell death, however we didn’t know that cancer cells use this tactic to avoid killing by the immune system.”
The researchers tested the importance of the TAK1 gene to cancer cell survival by silencing it using CRISPR/Cas9 technology. In pre-clinical models with typical immune function, they found that tumours lacking TAK1 grow poorly, demonstrating that the immune system is able to control cancer cells better.
Dr Huber says: “When TAK1 was blocked, immune signals generated by CD8+ T cells triggered the cancer cell’s self-destruct pathways.
“Without TAK1, the cancer cells lose a key protein, cFLIP, that normally prevents cell death, and they become far more sensitive to immune attack.”
Turning off TAK1 makes cancer cells much easier for the immune system to eliminate, offering hope for more powerful treatment options in the future.
Dr Tirta (Mario) Djajawi, Postdoctoral Researcher at ONJCRI, says: “Blocking TAK1 could make current immunotherapies more effective by stripping tumours of this protection.
“TAK1 is like a shock absorber that lets cancer cells survive the immune system’s hardest hits. Remove it, and the tumour collapses under the force of immune attack.”
Looking forward, the team will undertake further research into blocking TAK1 using innovative liquid nanoparticle technology and testing the efficacy of existing immunotherapies on cancer cells.
The research was conducted across a variety of cancer types, predominantly melanoma, which is often treated with immunotherapy and is diagnosed in 330,000 people worldwide and causes 60,000 deaths annually (2022 data).
This work was conducted in collaboration with Dr Stephin Vervoort’s laboratory and Sarahi Mendoza Rivera at WEHI.
Source:
Journal reference:
Djajawi, T. M., et al. (2025). A TAK1 cytokine toxicity checkpoint controls anti-cancer immunity. Cell Reports, [online] p.116665. doi:https://doi.org/10.1016/j.celrep.2025.116665. https://www.cell.com/cell-reports/fulltext/S2211-1247(25)01437-8
