OnCo
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Reprogramme suppressive macrophages instead of trying to delete them

Tumours fill with immune cells that protect them. Earlier drugs tried to remove those cells and failed. Newer ones aim to switch them to the attacking side.

CSF1R inhibitors depleted macrophages broadly and produced little benefit outside tenosynovial giant cell tumour, plausibly because depletion removes useful cells alongside harmful ones. TREM2, MARCO and LILRB2 mark specific suppressive macrophage states in human tumour single-cell atlases, and antibodies against them are in early trials. The proposition is state-switching, verified by on-treatment biopsies, rather than depletion.

Hypothesis
Blockade of a suppressive macrophage state marker shifts the intratumoural myeloid transcriptional programme towards antigen presentation and raises response to checkpoint blockade in tumours pre-selected for high suppressive macrophage content.
Rationale
Human single-cell data consistently identify TREM2-high macrophage states in poorly responding tumours, and genetic ablation in mice restores checkpoint response. Selecting patients by myeloid content, rather than treating everyone, is the step the CSF1R programmes skipped.
What would test it
A biopsy-mandated phase 2 in myeloid-high tumours with paired pre- and on-treatment single-cell profiling; kill the programme if the myeloid state does not shift, regardless of response rate.
Maturity
early clinical
Who has to act
industry
Cost to try
Medium ($1M to $50M)
Years to first evidence
6
Bottlenecks it attacks

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