Figure 2. The non-cell autonomous and the cell-autonomous effects of PI3K inhibitors.

PI3K inhibitors have well-studied cell-autonomous effects in cancer cells that lead to a cytostatic and cytotoxic response. These include the activation of intrinsic apoptosis, the reduction of glucose metabolism, translation inhibition, and changes in transcriptional regulation through the FOXO transcription factors among others. However, in addition to these effects, PI3K inhibitors can also exert non-cell autonomous affects in the organism and tumor microenvironment that can significantly contribute to the antitumoral effect. For example, administration of PI3K inhibitors lead to short and long-term metabolic responses that affect tumor nutrient availability and glycemic and insulinemic response. These compounds also have remarkable anti-angiogenic properties that are mediated by the alpha isoform. Inhibitors that target the delta and gamma isoform of PI3K inhibitors have been shown to affect macrophage activation (including polarization and phagocytosis), inhibition of regulatory T-cells, and inhibition of suppressive myeloid cells and neutrophils. Most of these changes result in activation of cytotoxic T-cells that promote cancer cell killing. The predominant PI3K isoform mediating each of these cellular effects have been highlighted in red (alpha), green (delta), and blue (gamma).