ERα-independent NRF2-mediated immunoregulatory activity of tamoxifen

Tamoxifen Twists Again: On and Off-Targets in Macrophages and Infections

“…Caspase-1 activation may eventually associate with cell death programs; however, IL-1β secretion can occur also independently from cell lysis ( Evavold et al, 2018 ). This latter mechanism has been observed for tamoxifen, which induces active caspase-1 formation in macrophages without affecting cell viability ( Pepe et al, 2021 ). A summary of the possible targets proposed by molecular and cellular studies for tamoxifen activity in macrophages is reported in Figure 2 .…”

“…It has been shown that GPER and ER β do not mediate the off-target macrophage responses to tamoxifen, since macrophages do not express ER β and GPER-selective activation elicits different responses as those induced by tamoxifen. Instead, the ER α -mediated effects of E 2 were inhibited by tamoxifen when assayed at 100-fold higher concentrations than nanomolar levels of the physiologic ligand, providing evidence for being an estrogen antagonist in innate immune cells ( Pepe et al, 2018 , 2021 ). Importantly, also ER α -independent responses were identified when using micromolar concentrations of tamoxifen.…”

“…The molecular mechanism of tamoxifen activity in macrophages was initially associated with the activation of PKC and transcription factors, such as GR, PPARy and STAT1 ( Komi et al, 2001 ; Jiang et al, 2013 ). More recently, the PI3K (phosphatidylinositol 3-kinase)/AKT pathway and NRF2 activation have also been proposed as additional immune targets of tamoxifen, increasing the expression of NRF2 target genes, such as Hmox-1 (heme oxygenase 1), or Vegf-a (vascular endothelial growth factor A) and inhibiting other immune polarization markers such as Il-1b or Arg-1 (arginase 1) ( Feng et al, 2018 ; Pepe et al, 2021 ). This finding is particularly interesting, considering that NRF2 activation in macrophages prompts protective responses against infections through phagocytosis and autophagy of bacterial or viral particles, induction of intracellular detoxification reactions and potentiation of the inflammatory response ( Hai et al, 2011 ; Harvey et al, 2011 ; Mornata et al, 2020 ; Furuya et al, 2016 ; Bewley et al, 2018 ; Zhao et al, 2014 ).…”

“…Notably, drug activity in macrophages has been recently extended to immune-metabolic responses. In fact, tamoxifen was shown to potentiate the M1 phenotype, increase phagocytosis and induce active caspase-1 formation ( Pepe et al, 2021 ). Transformation of caspase-1 precursor into the active enzyme promotes IL-1β maturation and secretion by macrophages, thus controlling pathogen infections ( Man, Karki, and Kanneganti 2017 ).…”

Tamoxifen Modulates the Immune Landscape of the Tumour Microenvironment: The Paired Siglec-5/14 Checkpoint in Anti-Tumour Immunity in an In Vitro Model of Breast Cancer

“…Several studies showed that the immune consequences of TMX exposure in macrophages are expressed as the potentiation of the inflammatory response, autophagy and phagocytosis regulated by off-target mechanisms. The study by Pepe et al demonstrated that TMX promotes the maturation of IL-1β and its secretion by the macrophages as a result of its direct influence on the formation of caspase-1 [ 41 ]. According to Sfogliarini et al, the phosphatidylinositol 3-kinase/nuclear factor erythroid 2-related factor 2 (PI3K-NRF2) pathway and multiple molecular mediators, including protein kinase C (PKC) and oxidative stress molecules, may represent a host-mediated mechanism that leads to the beneficial TMX-induced immune activity against pathogens [ 40 ].…”