CXCL9:SPP1 macrophage polarity identifies a network of cellular programs that control human cancers

Science. 2023 Aug 4;381(6657):515-524. doi: 10.1126/science.ade2292. Epub 2023 Aug 3.


Tumor microenvironments (TMEs) influence cancer progression but are complex and often differ between patients. Considering that microenvironment variations may reveal rules governing intratumoral cellular programs and disease outcome, we focused on tumor-to-tumor variation to examine 52 head and neck squamous cell carcinomas. We found that macrophage polarity-defined by CXCL9 and SPP1 (CS) expression but not by conventional M1 and M2 markers-had a noticeably strong prognostic association. CS macrophage polarity also identified a highly coordinated network of either pro- or antitumor variables, which involved each tumor-associated cell type and was spatially organized. We extended these findings to other cancer indications. Overall, these results suggest that, despite their complexity, TMEs coordinate coherent responses that control human cancers and for which CS macrophage polarity is a relevant yet simple variable.

MeSH terms

  • Cell Polarity* / immunology
  • Chemokine CXCL9* / analysis
  • Chemokine CXCL9* / metabolism
  • Head and Neck Neoplasms* / immunology
  • Head and Neck Neoplasms* / pathology
  • Humans
  • Macrophages* / immunology
  • Osteopontin* / analysis
  • Osteopontin* / metabolism
  • Prognosis
  • Squamous Cell Carcinoma of Head and Neck* / immunology
  • Squamous Cell Carcinoma of Head and Neck* / pathology
  • Tumor Microenvironment*


  • Chemokine CXCL9
  • CXCL9 protein, human
  • Osteopontin
  • SPP1 protein, human