Summary
A preclinical study found that activating PPARδ in immune cells improved tumour control and checkpoint therapy responses in mouse models of immune-evasive colorectal cancer. Experiments with human cells and tumour organoids also showed stronger anti-tumour activity.
A study in Nature Immunology reports that activating the lipid-sensing protein PPARδ in immune cells helped control tumours and improved responses to checkpoint immunotherapy in mice. The same pathway had the opposite effect when activated in cancer cells: it promoted their growth. The findings point to cell-selective PPARδ activation as a possible way to strengthen anti-tumour immunity, but the evidence is preclinical.
The effect depends on which cells activate PPARδ
PPARδ is a transcription factor, a protein that helps regulate which genes are active. It responds to lipids and influences fatty-acid oxidation (FAO), the process by which cells break down fatty acids for energy. The researchers used genetic models to activate PPARδ separately in cancer cells or immune cells.
In mouse colorectal cancer models, activating PPARδ in cancer cells increased tumour growth and was associated with gene activity linked to cancer-cell survival, proliferation and immune suppression. Activating it in immune cells instead slowed tumour growth, including in an aggressive model of microsatellite-stable (MSS) colorectal cancer. MSS tumours commonly resist existing immunotherapies. The immune-cell effect also reduced metastasis in the mouse model and was seen in models of melanoma and breast cancer.
The researchers traced much of the immune response to CD8+ T cells, which can recognise and kill abnormal cells. When PPARδ was activated in these cells, they were more abundant in tumours and showed increased activity associated with tumour killing. The study’s single-cell analyses also found changes in gene expression and chromatin accessibility—the openness of DNA regions that can affect whether genes are used—at sites associated with T-cell effector function.
PPARδ increased Cpt1a activity and FAO in CD8+ T cells. Removing Cpt1a weakened parts of the PPARδ-driven response, including T-cell infiltration and tumour control. But activating Cpt1a by itself did not reproduce the full effect of PPARδ, suggesting that the pathway also acts through other metabolic or gene-regulatory changes.
Checkpoint therapy and human-cell experiments
In mice with established MSS colorectal tumours, researchers transferred CD8+ T cells with genetically activated PPARδ and treated the animals with the checkpoint inhibitor anti-PD-1. Half of the mice receiving the modified cells had rejected their tumours by day 35. In that experiment, overall survival did not significantly improve. In a separate experiment, combining the transferred cells with anti-PD-1 and anti-CTLA4 improved survival compared with transfer of unmodified CD8+ T cells.
Experiments involving human cells offer an early indication that the effect may extend beyond mouse immune cells. Treating human immune cells with the PPARδ agonist GW501516 before co-culture increased their killing of patient-derived colorectal tumour organoids, including MSS and microsatellite-instable samples. Human CAR-T cells—T cells engineered to recognise a tumour target—also showed increased tumour-cell killing after pharmacological or genetic PPARδ activation. In mice bearing ovarian tumour cells, transferred human CAR-T cells engineered to activate PPARδ reduced tumour growth.
These results come from mouse models, laboratory co-cultures and a mouse experiment using human CAR-T cells, not a clinical trial. The genetic approach used an engineered VP16/VP64–PPARδ activator, while some human-cell experiments used a drug agonist; the study does not establish a treatment method for patients. Selectivity is central: activating PPARδ in tumour cells promoted growth in the experiments, so a therapeutic approach would need to strengthen immune cells without producing the same effect in cancer cells. The tested mouse models showed no overt systemic inflammatory toxicity, while the researchers note that longer-term safety studies are needed.