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Emerging roles of class I PI3K inhibitors in modulating tumor microenvironment and immunity

Abstract

Immune system-mediated tumor killing has revolutionized anti-tumor therapies, providing long-term and durable responses in some patients. The phosphoinositide 3-kinase (PI3K) pathway controls multiple biological processes and is frequently dysregulated in malignancies. Enormous efforts have been made to develop inhibitors against class I PI3K. Notably, with the increasing understanding of PI3K, it has been widely accepted that PI3K inhibition not only restrains tumor progression, but also reshapes the immunosuppressive tumor microenvironment. In this review, we focus on the pivotal roles of class I PI3Ks in adaptive and innate immune cells, as well as other stromal components. We discuss the modulation by PI3K inhibitors of the tumor-supportive microenvironment, including eliminating the regulatory immune cells, restoring cytotoxic cells or regulating angiogenesis. The potential combinations of PI3K inhibitors with other therapies to enhance the anti-tumor immunity are also described.

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Fig. 1: The PI3K/AKT/mTOR signaling pathway in cancer.
Fig. 2: Pleiotropic modulation of the tumor-immune interface by PI3K inhibitors.

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Acknowledgements

This work was supported by “Personalized Medicines-Molecular Signature-based Drug Discovery and Development”, Strategic Priority Research Program of the Chinese Academy of Sciences [XDA12020111, XDA12020235, and XDA12050407]; National Science and Technology Major Project “Key New Drug Creation and Manufacturing Program” [2018ZX09711002-011-014 and 2018ZX09711002-004-004] and National Natural Science Foundation of China [81773760 and 81973345]. It was also partially supported by the Fudan-SIMM Joint Research Fund [FU-SIMM20172005].

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Correspondence to Ling-hua Meng.

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Sun, P., Meng, Lh. Emerging roles of class I PI3K inhibitors in modulating tumor microenvironment and immunity. Acta Pharmacol Sin 41, 1395–1402 (2020). https://doi.org/10.1038/s41401-020-00500-8

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Keywords

  • phosphoinositide 3-kinase (PI3K)
  • PI3K inhibitors
  • tumor microenvironment
  • immune cells
  • immunotherapy

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