Immuno-Metabolism and Microenvironment in Cancer: Key Players for Immunotherapy

Gaia Giannone, Eleonora Ghisoni, Sofia Genta, Giulia Scotto, Valentina Tuninetti, Margherita Turinetto, Giorgio Valabrega

Research output: Contribution to journalReview articlepeer-review


Immune checkpoint inhibitors (ICIs) have changed therapeutic algorithms in several malignancies, although intrinsic and secondary resistance is still an issue. In this context, the dysregulation of immuno-metabolism plays a leading role both in the tumor microenvironment (TME) and at the host level. In this review, we summarize the most important immune-metabolic factors and how they could be exploited therapeutically. At the cellular level, an increased concentration of extracellular adenosine as well as the depletion of tryptophan and uncontrolled activation of the PI3K/AKT pathway induces an immune-tolerant TME, reducing the response to ICIs. Moreover, aberrant angiogenesis induces a hypoxic environment by recruiting VEGF, Treg cells and immune-suppressive tumor associated macrophages (TAMs). On the other hand, factors such as gender and body mass index seem to affect the response to ICIs, while the microbiome composition (and its alterations) modulates both the response and the development of immune-related adverse events. Exploiting these complex mechanisms is the next goal in immunotherapy. The most successful strategy to date has been the combination of antiangiogenic drugs and ICIs, which prolonged the survival of patients with non-small-cell lung cancer (NSCLC) and hepatocellular carcinoma (HCC), while results from tryptophan pathway inhibition studies are inconclusive. New exciting strategies include targeting the adenosine pathway, TAMs and the microbiota with fecal microbiome transplantation.

Original languageEnglish
JournalInternational Journal of Molecular Sciences
Issue number12
Publication statusPublished - Jun 21 2020


  • Animals
  • Humans
  • Immune Checkpoint Inhibitors/pharmacology
  • Immunotherapy/methods
  • Neoplasms/immunology
  • Signal Transduction/drug effects
  • Tumor Microenvironment/drug effects
  • Tumor-Associated Macrophages/drug effects


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