Fig. 10: The multifaceted role of estrogen in regulating an immunosuppressive TIME in the liver.

Shown is a diagrammatic representation of postulated mechanisms that may be underlying the observed estrogen-mediated regulation of an immunosuppressive TIME in the liver. The ER/E2 signaling pathway can promote metastatic expansion in the liver by inducing TNFR2 transcription. In turn, TNFR2 may rescue immune cells from TNFR1-mediated death signals triggered by the TNF-α-rich microenvironment of LM and/or initiate signal transduction, leading to transcriptional activation of immunosuppressive gene products. This favors MDSC survival and suppressive activity, and reduces CD8⁺T-cell-mediated antitumor responses. ER signaling (possibly in conjunction with, or independently of TNFR2) also regulates transcription of immunosuppressive proteins in the liver to enhance immune evasion. Tamoxifen treatment blocks the ER/E2 axis and reduces immune tolerance to improve tumor cell clearance (dashed lines indicate postulated molecular pathways).