A faulty brake signal in the gut's stem cells—the WNT pathway stuck in the "on" position—shuts out the immune system's killer T cells, protecting tumours from attack. This happens in about 80% of colorectal cancers, where a mutation in the *APC* gene locks WNT signalling into overdrive. The problem is that current immunotherapies, which work well against cancers like melanoma, fail in most colorectal cancer patients precisely because their tumours carry this high-WNT signature. The research team has discovered that WNT-driven immune evasion is not just a cancer trick—it also occurs in normal intestinal crypts and during injury-induced regeneration, suggesting it is a hijacked physiological mechanism. If the team can pinpoint how WNT activation excludes T cells, they could design therapies that re-sensitise these tumours to immune checkpoint inhibitors without poisoning healthy stem cells. This is fundamental science with a clear clinical target: turning immunologically "cold" colorectal cancers into "hot" ones that respond to treatment, potentially benefiting the large majority of patients whose tumours carry WNT-activating mutations.
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WNT signalling plays a critical role in normal in WNT signalling plays a critical role in normal intestinal homeostasis, regeneration and tumorigenesis. WNT is required for intestinal stem cell maintenance and injury-induced regeneration, while aberrant WNT activation causes cancer. Specifically, APC-truncating mutation are detected in ~80% of colorectal cancer (CRC), leading to hyperactivation of WNT signalling. Despite decades of research, targeting WNT signalling remains challenging due to on-target toxicity in stem cell compartments. Targeting WNT in CRC remains an unmet need. Immune checkpoint inhibition (ICI) shows remarkable responses in solid cancers such as melanoma. However, the majority of CRC patients with high WNT signature do not respond to current ICI strategies. Genomic analysis of the clinical data shows that the "T cell-inflamed" phenotype and WNT-low signature are the two strongest predictors of ICI response in multiple cancer types, suggesting a link between the two. Understanding the underlying biological processes appears fundamental to the development of immunotherapies and will benefit a large proportion of patients with WNT-activated tumour. Our preliminary data show that WNT activation causes cytotoxic T cell (CTL) exclusion not only in CRC, but also in normal WNT-high intestinal crypts and in WNT-dependent irradiation-induced regeneration, suggesting that the role of WNT signalling in subverting immune responses is a physiological mechanism, highjacked by cancers. We propose a unique approach to study the mechanisms underlying WNT activation and the associated immunosuppression in normal intestine, regeneration and cancer. These insights will guide the development of tumour-specific therapies to sensitise ICI response in WNT-activated CRCs and other cancers with minimal toxicity. Our extensive expertise in WNT signalling, intestinal stem cell, CRC and organoid research will place us in a unique position to study WNT-mediated immune evasion.
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