Targeting macrophage-derived SPP1 enhances CD8 T cell infiltration via ROS-DNA fragment/cGAS-STING/STAT1-mediated...

Area of Science:

• Immunology
• Oncology
• Cell Biology

Background:

• Elevated SPP1+ tumor-associated macrophages (TAMs) correlate with reduced CD8+ T cell infiltration and poor cancer prognosis.
• The exact mechanisms by which SPP1+ TAMs exclude CD8+ T cells and regulate T cell trafficking are not fully understood.

Purpose of the Study:

• To investigate the causal role of macrophage SPP1 in regulating CD8+ T cell infiltration and tumor progression.
• To elucidate the molecular mechanisms underlying SPP1-mediated regulation of T cell trafficking in the tumor microenvironment.

Main Methods:

• Established multiple tumor mouse models to study macrophage SPP1 function.
• Utilized single-cell RNA sequencing on clinical and mouse tumor samples.
• Performed Western blotting, immunofluorescence staining, and flow cytometry.

Main Results:

• Macrophage-derived SPP1 suppresses CD8+ T cell infiltration, promotes tumor growth, and reduces ICI therapy efficacy.
• Genetic deletion of SPP1 in macrophages enhances CD8+ T cell infiltration and tumor suppression via CD8+ T cell-mediated immunity.
• SPP1 deficiency in macrophages increases ROS, leading to dsDNA accumulation, cGAS-STING activation, STAT1 phosphorylation, and CXCL9/10 upregulation, facilitating CD8+ T cell recruitment.

Conclusions:

• Deletion of SPP1 in TAMs enhances CD8+ T cell infiltration by activating the ROS-DNA fragment/cGAS-STING/STAT1 pathway.
• This mechanism upregulates CXCL9/10, improving anti-tumor immunity and ICI treatment outcomes.