Cancer's immune guards are the new drug target
In glioblastoma, prostate cancer, neuroblastoma and breast cancer, the cells that shield tumours from immunotherapy are coming into focus — and so are ways to remove them.
- Knocking down S100A4 in glioma cells drew in CD8 T cells and matured antigen-presenting cells in mouse models, in a preprint. Self-reported m:…6406
- In BRCA2-deficient prostate cancer models, anti-PD-1 monotherapy expanded CCR8-positive regulatory T cells; depleting them restored checkpoint sensitivity, in a preprint. Self-reported m:…6402
- Neuroblastoma tissue cores showed few infiltrating T cells and abundant macrophages carrying CD40, CSF1R, CD163 and Clever-1, in a preprint analysis of 185 cores. Self-reported m:…6404
- Tet2-mutant clonal haematopoiesis drove breast cancer progression in aged mice while Dnmt3a-mutant haematopoiesis prevented it, in a preprint. Self-reported m:…6298
- PIK3CA mutations promoted resistance to the pan-RAS inhibitor daraxonrasib in colorectal cancer; combined RAS and PI3K inhibition induced apoptosis, in a preprint. Self-reported m:…6408
The guards, not the tumour
Glioblastoma barely responds to checkpoint blockade, and a preprint posted this week points at a protein called S100A4 as one reason why. In mouse models, knocking down S100A4 in glioma cells reprogrammed the tumour microenvironment, drawing in more CD8 T cells and maturing antigen-presenting cells. A new S100A4/TfR bispecific antibody combined with anti-PD-1 treatment generated tertiary lymphoid-like structures inside the tumour — the organised immune outposts that checkpoint drugs need to work with. m:…6406
The same pattern shows up in children. An analysis of 185 neuroblastoma tissue cores found a tumour microenvironment with few infiltrating T cells and abundant tumour-associated macrophages, carrying targetable receptors including CD40, CSF1R, CD163 and Clever-1. The CD47-positive fraction was enriched in stage IV disease and predicted worse overall survival. Chemotherapy, the study reports, shifted the microenvironment further toward a macrophage-dominated, lymphocyte-depleted profile — treatment itself may be strengthening the guard. m:…6404
Checkpoint drugs can feed the guard
In BRCA2-deficient prostate cancer, the guard is a regulatory T cell. The preprint reports that BRCA2 loss activates the cGAS/STING pathway and a type I interferon response, producing an immunosuppressive microenvironment enriched with CCR8-positive regulatory T cells. Anti-PD-1 monotherapy not only failed in this model — it expanded the CCR8-positive regulatory T cell population further. Depleting those cells restored sensitivity to checkpoint blockade. m:…6402
That is the uncomfortable version of the story: the drug meant to release the immune system can feed the cells suppressing it. It explains why a mutation that should make a tumour more visible to the immune system — BRCA2 loss creates genomic instability — can instead make it more resistant. The target is no longer just the checkpoint. It is the cell type the checkpoint drug accidentally grows. m:…6402
The same mutation, opposite effects
A fourth preprint adds a twist from outside the tumour entirely. Clonal haematopoiesis — blood stem cells carrying mutations, common with age — changed breast cancer progression in aged mice in opposite directions depending on the mutation. Tet2-mutant blood cells drove progression through immunosuppressive macrophages producing IL-1 and CXCL2 with low MHCII expression, while Dnmt3a-mutant blood cells prevented progression, recruiting CD8 T cells through macrophages with high MHCII. Blocking IL-1R1 or CXCR2 reduced tumour progression in the Tet2-mutant mice. m:…6298
The implication is that a patient's blood, not just their tumour, may decide whether immunotherapy works — and that the same test result, clonal haematopoiesis, means opposite things depending on which gene is mutated. For drug developers, that turns a biomarker into a fork in the road: IL-1 and CXCR2 blockade look like the combination to test in Tet2-mutant disease, and a dead end in Dnmt3a-mutant disease. m:…6298
Resistance inside the cancer cell too
Not all resistance runs through the immune system. In KRAS/PIK3CA co-mutated colorectal cancer, a preprint reports that PIK3CA mutations promote resistance to the pan-RAS inhibitor daraxonrasib by sustaining PI3K-AKT signalling and remodelling cell-cell adhesion. Combined RAS and PI3K inhibition suppressed signalling and induced apoptosis in the co-mutant cells — the combination, not the single drug, is the answer the biology points to. m:…6408
Five preprints, one thread: resistance to cancer therapy keeps tracing back to the cells and pathways around the drug's target, not the target itself. The companies that win the next round of combination trials will be the ones that read the microenvironment first and pick the partner drug second. m:…6406 m:…6408
What is still unresolved
- Whether S100A4 blockade works in human glioblastoma as it did in mice
- Whether CCR8-positive regulatory T cell depletion is safe alongside checkpoint blockade in patients
- How often clonal haematopoiesis mutation status is measured in cancer trials today
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