In situ CAR engineering and nanoparticle-mediated TREM2 degradation for macrophage reprogramming in malignant ascites.

Lipid nanoparticles delivering Claudin18.2 CAR mRNA plus a TREM2 ligand drive TREM2 internalization and degradation in TREM2+ tumour-associated macrophages, reprogramming them and boosting CD8+ responses.

• Why it matters: Peritoneal metastasis and malignant tumour ascites in advanced gastrointestinal cancers show ~90% enrichment of TREM2+ tumour-associated macrophages that support CD8+ T cell dysfunction and tumour growth.
• What they did: The approach uses mRNA-encoded CAR macrophage reprogramming in malignant tumour ascites, with a piperazine-containing phosphoramide ionizable lipid designed to synergize with the TREM2 ligand to inhibit dissociation and promote lysosomal/autophagosomal degradation.
• The result: This suppresses AKT signalling, shifts macrophages toward an antitumour phenotype, reduces immunosuppression, and—combined with PD-1 blockade—suppresses tumour growth and extends survival in mice with matching immunological effects in clinical samples.

AI summary of the abstract · may contain errors · not medical advice · read the paper.