The tumor microenvironment (TME) is a complex network, which includes soluble factors and components of the extracellular matrix as well as stromal, endothelial and immune cells. Immune cells and, among them, myeloid cells, play important roles in cancer development and can promote or inhibit cancer initiation and progression. Among tumor-infiltrating immune cells, macrophages are well-known determinants of cancer-related inflammation and are typically characterized by their remarkable plasticity. This consists in the ability to acquire a wide spectrum of activation states in response to various signals derived from the microenvironment. Classical M1 and alternative M2 macrophages represent the paradigm of this property. Tumor-associated macrophages (TAMs) usually display a so-called “M2-like” phenotype that can foster tumor progression in different ways, namely by promoting genetic instability, angiogenesis and metastasis and by restraining anti-tumor adaptive immunity. Notably, TAMs can also play a dual role in the response to conventional anti-tumor therapies: they can enhance the anti-neoplastic effect, or, in contrast, they can sustain a tumor-promoting response and so foil the anti-cancer power of these drugs. We recently identified IL-1R8, which we had cloned as TIR8 and is also known as SIGIRR, as a checkpoint in NK cells, which negatively regulates response to myeloid derived IL-18. Unleashed NK cells mediate resistance to liver carcinogenesis and metastasis at NK rich anatomical sites. Thus, the organ immunological context is a key determinant of the role of innate and adaptive immunity in tumor progression.


  1. Molgora M, Bonavita E, Ponzetta A, Riva F, Barbagallo M, Jaillon S, Popovic B, Bernardini G, Magrini E, Gianni F, Zelenay S, Jonjic S, Santoni A, Garlanda C, Mantovani A. IL-1R8 is a checkpoint in NK cells regulating anti-tumor and anti-viral activity. Nature 551:110-114, 2017.
  2. Mantovani A., Marchesi F., Laghi L., Malesci A., Allavena P.   Tumor-associated macrophages as treatment targets in oncology. Nature Rev, Clin. Oncol.;  14(7):399-416, 2017.
  3. Bonavita E, Gentile S, Rubino M, Maina V, Papait R, Kunderfranco P, Greco C, Feruglio F, Molgora M, Laface I, Tartari S, Doni A, Pasqualini F, Barbati E, Basso G, Galdiero MR, Nebuloni M, Roncalli M, Colombo PG, Laghi L, Lambris JD, Jaillon S, Garlanda C, Mantovani A.   PTX3 is an extrinsic oncosuppressor regulating complement-dependent inflammation in cancer. Cell  160: 700-714, 2015.
  4. Mantovani A, Allavena P, Sica A, Balkwill F  Cancer-Related Inflammation. Nature 454: 436-444, 2008.