Cancer Immunol Res. 2026 Mar 19. doi: 10.1158/2326-6066.CIR-25-1138. Online ahead of print.
ABSTRACT
The variation in immunotherapy responses among patients with triple-negative breast cancer (TNBC) is attributed to the high heterogeneity of tumor immune components, in which macrophages play a key role. Hence, identification of key macrophage subpopulations associated with immunotherapy efficacy could provide important biological and therapeutic insights. Here, using single-cell and spatial transcriptomes, we identified at the single-cell level, a subpopulation of macrophages related to T cell expansion during immunotherapy, characterized by high temperature requirement A1 (HTRA1) high expression and correlated with clinical and immunotherapy outcomes in TNBC. Loss of macrophage-specific Htra1 in transgenic mouse resulted in delayed TNBC growth, improved immunotherapy efficacy, and increased CD8+ T cell infiltration. Mechanistically, HTRA1 associated with cysteine-rich protein 1 (CRIP1) to facilitate CRIP1 binding to NF-κB, thereby activating NF-κB pathway and downstream CXCL12 transcription, leading to T cell exit from tumors. Endothelial cell-derived CX3CL1 was implicated in the recruitment of HTRA1+ macrophages to tumor sites. Pharmacological antagonism of CXCL12/CXCR4 axis potentiated the immunotherapy efficacy in orthotopic TNBC mouse models. In conclusion, this study highlights a HTRA1+ macrophage subpopulation that can limit T cell infiltration and immunotherapy efficacy via the CXCL12/CXCR4 axis, which offers new leads to improve immunotherapeutic interventions in TNBC.
PMID:41854522 | DOI:10.1158/2326-6066.CIR-25-1138