Targeting VSIG4 tissue-resident macrophages enhances T cell cytotoxicity and immunotherapy efficacy in cancer.

Tissue-resident macrophage (TRM) is crucial for organ development and homeostasis. However, the role of TRM-derived tumor-associated macrophage (TAM) subpopulations in cancer remains unclear. Using single-cell RNA sequencing and lineage tracing, we reported a TRM-derived TAM subpopulation, characterized by VSIG4 overexpression in testicular cancer. Macroscopically, such subpopulation was also found in tumors such as hepatocellular carcinoma, lung cancer, and glioblastoma. It was associated with poor prognosis and the suppression of CD8 T-cell-dependent immunity via VSIG4. Notably, VSIG4 promoted immunosuppressive effects through direct or indirect modes, including interacting with receptors on CD8 T cells or inducing transcription of IL-11 in TAMs. More importantly, MEF2C was identified as a key transcription factor that maintained VSIG4 expression and determined the biological behaviors of VSIG4 TAMs. In preclinical models, targeting VSIG4 TAMs via VSIG4 or MEF2C demonstrated a favorable effect of enhancing the efficacy of immune checkpoint inhibitors.