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

Abstract

Peritoneal metastasis (PM) and the resulting malignant tumour ascites characterize advanced gastrointestinal cancers, often leading to poor prognosis and limited response to current therapies. Single-cell analysis of patient-derived PM and malignant tumour ascites reveals an approximately 90% enrichment of TREM2+-tumour-associated macrophages, which drive CD8+ T cell dysfunction and tumour growth. Here we develop lipid nanoparticles encapsulating mRNA to reprogram these tumour-associated macrophages into chimeric antigen receptor macrophages targeting Claudin18.2-positive tumour ascites. The lipid nanoparticles incorporate a TREM2+ ligand to enhance the targeting of TREM2 macrophages. The piperazine-containing phosphoramide ionizable lipid synergizes with the TREM2 ligand to inhibit ligand dissociation, promoting TREM2 internalization and degradation via lysosomal and autophagosomal pathways. This inhibits AKT signalling and reprograms tumour-associated macrophages towards an antitumour phenotype, enhancing progenitor exhausted and effector memory CD8+ T cell responses, altering the PM transcriptome, and reducing immunosuppression in both malignant tumour ascites and tumours. Combined with PD-1 blockade, this therapy suppresses tumour growth and extends survival in mice, and with matching immunological effects in clinical samples, demonstrates its translational potential for PM immunotherapy.

Abstract as supplied by the indexing source. © the authors / publisher.