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Estrogen/ER in anti-tumor immunity regulation to tumor cell and tumor microenvironment


As the essential sexual hormone, estrogen and its receptor has been proved to participate in the regulation of autoimmunity diseases and anti-tumor immunity. The adjustment of tumor immunity is related to the interaction between cancer cells, immune cells and tumor microenvironment, all of which is considered as the potential target in estrogen-induced immune system regulation. However, the specific mechanism of estrogen-induced immunity is poorly understood. Typically, estrogen causes the nuclear localization of estrogen/estrogen receptor complex and alternates the transcription pattern of target genes, leading to the reprogramming of tumor cells and differentiation of immune cells. However, the estrogen-induced non-canonical signal pathway activation is also crucial to the rapid function of estrogen, such as NF-κB, MAPK-ERK, and β-catenin pathway activation, which has not been totally illuminated. So, the investigation of estrogen modulatory mechanisms in these two manners is vital for the tumor immunity and can provide the potential for endocrine hormone targeted cancer immunotherapy. Here, this review summarized the estrogen-induced canonical and non-canonical signal transduction pathway and aimed to focus on the relationship among estrogen and cancer immunity as well as immune-related tumor microenvironment regulation. Results from these preclinical researches elucidated that the estrogen-target therapy has the application prospect of cancer immunotherapy, which requires the further translational research of these treatment strategies.


The immune response differs with male and female. It has reported that females have the advantage in antimicrobic immunity and anti-tumor immunity, while females also suffer from the higher susceptibility to the autoimmune diseases (AD) [1]. Except for physiological structure variation on male and female, the gender-based immunity diversity is showed to account for the difference of sexual hormone secretion, such as estrogen, progestogen and androgen. However, the function of estrogen in cancer research still emphasized on the cancer cell proliferation [2], angiogenesis [3], epithelial–mesenchymal transition (EMT) [4], while the estrogen-induced cancer immune response alternation remains unclear. This review emphasized on the cell modification induced by estrogen and its receptor, estrogen receptor (ER), in canonical and non-canonical manner. On the other hand, the estrogen-related anti-tumor immunity regulation in different tumor microenvironment (TME) components was elucidated, including cancer cells, T cells, tumor-associated macrophages (TAM), cancer-associated fibroblasts (CAFs), and collagen in tumor tissues. These results suggested the potential for estrogen and ER as the therapeutic target in the cancer immunotherapy.

Estrogen and estrogen receptor

Estrogen, which is mainly produced by the ovary and placenta of female animals, acts as a critical hormone that promotes the development of secondary sexual characteristics and maturation of sexual organs [5]. The biosynthesis relies on the function of CYP19a1, also called aromatase, performing the conversion from testosterone to estrogen [6]. The study found that the expression of CYP19a1 exists in different tissues in human, including liver, muscle, placenta, bone, breast, adipose tissue, and brain [7, 8]. So, it is not surprised that the sites of estrogen production are widely distributed over the different human organs and tissues. Multiple types of estrogen participate in estrogen metabolic process, including 13 known estrogen metabolites with different hydroxylation at the steroid ring, such as estrone, estradiol and estriol and so on [9]. CYP19a1 catalyzes the C19 aromatization of androstenedione and synthesizes the estrone. Then, estrone will consequently transform into estradiol and estriol. Among these estrogen types, 17β-estradiol (E2) is the most common estrogen form in human and has the potent function in estrogen pathway activation, which has the highest priority binding with estrogen receptor than estrone or estriol [10, 11]. E2 is mainly secreted by the ovaries and regulated by luteinizing hormone (LH) and follicle-stimulating hormone (FSH) during the menstrual cycle [12, 13]. The dramatic decay of E2 occurs in menopause while the concentration of estrone has only modest decline [14]. The alternation of estrogen causes the osteoporosis, senile vaginitis, cardiac symptoms and other menopausal syndrome.

The estrogen-induced targeted genes transcription relies on its binding with its receptor, called estrogen receptor (ER). The classical ER in mammal is divided into two distinct subtypes, ERα and ERβ, which are encoded by ESR1 and ESR2 and control the biological effects in vivo by recognizing estrogen in target tissues [15, 16]. These classical ERs mainly express in plasma membrane and nucleus, which contain a DNA-binding domain [17]. After activated by estrogen, the complex of estrogen and ER transfers to nuclear and locates to the estrogen response elements (ERE) in the distal enhancer regions of target genes [18]. Together with the coordinate regulators (p300/CBP, c-Jun, GATA3 and FOXA1), the activated ER enhancer regulates the genomic remodeling, including open chromatin architecture, histone modifications and trigger the ER-dependent genes transcription [19, 20]. On the other hand, the ER enhancer is able to connect with RNA polymerase II and promotes a series of noncoding enhancer RNAs transcription, called enhancer RNA (eRNA) [21]. The function of eRNA is still unclear. Some studies revealed that eRNA may regulate the gene transcription function by enhancing the strength of specific enhancer-promoter looping [22]. However, Rahman and his colleagues proved that eRNA-induced enhancer-promoter loops are unnecessary for the maintain of transcription by single-cell profiling [23]. Thus, the research in eRNA function in ER-induced regulation is a matter of considerable recent interest.

Besides the typical nuclear ER, it has been reported that membrane estrogen receptor (mER) also participated in the regulation of estrogen pathway. G Protein-Coupled Estrogen Receptor 1 (GPER1), also known as GPR30, is a member of G protein-coupled receptors located in on 7p22.3 chromosome, which is reported as a new membrane estrogen receptor in human [24, 25]. GPER1 has high affinity with estrogen and results to the rapid signal transduction by activating the cAMP, intracellular calcium and tyrosine kinase Src without DNA interaction [24]. Interestingly, Toran-Allerand found a novel mER called “ER-X”, which was mainly expressed in brain and uterus, especially in brain disorders. Although it shares some homology with ERα, the knock-out of ERα still has no influence on the expression of ER-X, suggesting the difference between ER-X and typical nuclear ER [26, 27]. However, until now, the ER-X is still unidentified, which requires further confirmed in the future.

Signal pathway induced by estrogen in cancer

NF-κB pathway

nuclear factor kappa-B (NF-κB) pathway controls the cytokine secretion, cell survival and proliferation, playing a critical role in inflammation development and immune regulation in TME [28, 29]. Estrogen receptor inhibits the expression level of Fos-related antigen 2 (Fra2) and down-regulates the NF-κB pathway. Both Fra2 and NF-κB synergistically promote the expression of RelB and Bcl-2, facilitating the EMT and bone metastasis in breast cancer [30, 31]. On the other hand, GPER enhances the phosphorylation of ERK and AKT and promotes the nuclear translocation of p65 as well as phosphorylation of IκB kinase β (IKK-β) after activation by specific GPER agonist, cadmium or G-1 [32, 33]. The phosphorylation and nuclear localization of NF-κB interact with IL-6 and contribute to angiogenesis and invasiveness in tumor progression, which can be reversed by G-1 [34]. However, the researches in breast cancer indicated that E2 reverses the anti-tumor effect of TNF-α by inhibiting NF-κB and further inactivating IAP, which blocks the process of tumor cells apoptosis [35]. Yang and his colleagues found that the knock-down of ERβ increases the expression of AKT and subsequently activates the phosphorylation of p65 in osteosarcoma. The ERβ-deficient osteosarcoma cells reveal a high level of proliferation, which can be reversed by PI3K inhibitor LY294002, indicating the key regulation in ERβ-induced PI3K-AKT- NF-κB pathway [36].

MAPK–ERK pathway

Mitogen-Activated Protein Kinases (MAPKs), also known as extracellular signal-regulated kinases (ERKs), act as a regulator of cancer cell proliferation [37], differentiation [38] and metastasis [39]. The activation of ERK/MAPK depends on the stimulation of multiple growth factors, cytokines, viruses, G-protein-coupled receptor ligands and oncogenes, including epidermal growth factor (EGF), tumor necrosis factor (TNF), activators of protein kinase C (PKC) and Src family members [40]. In triple-negative breast cancer cell lines, MDA-MB-231 and MDA-MB-436, ER-α36 and EGFR are highly expressed while ER-α66 and ER-α46 are depleted. So, the treatment of E2 up-regulates the phosphorylation of ERK1/2 (p-ERK1/2) in dose-dependent manner and the decay of ER-α36 can reverse the E2-induced p-ERK1/2 activation [41]. Similar results are also reported in cervical cancer cells research, including CaSki and HeLa, which further confirmed the key function of ER-α36 in E2-induced ERK pathway activation [42]. The function of nuclear estrogen receptors also needs the mediation of insulin-like growth factor-1 (IGF-1). IGF-1R causes the mobilization of MAPK pathway and promotes the neuroestrogen synthesis and estrogen-induced targeted gene transcription, which is antagonised by PI3K [43]. On the other hand, the treatment of estrogen promotes the production of reactive oxygen species (ROS) and mediates the activation of p38 MAPK, which can be abolished by antioxidant, NAC. Furthermore, Estrogen-induced p38 MAPK enhances the expression of p21 in hypoxia and reduces the proliferation of breast cancer by G1/S phase cell cycle arrest, suggesting the proliferation adjustment in MAPK pathway induced by estrogen [44].

β-catenin pathway

The Wnt/β-catenin pathway plays an important role in development, tissue renewal, cell proliferation and differentiation, and its deregulation is associated with numerous diseases [45, 46]. Guo’s research found that the treatment of Bisphenol A, a weak estrogen agonist, promotes the expression of β-catenin and causes elevated expression of cancer stem cell markers, accelerating the human ovarian cancer cell-derived sphere formation [47]. In ER−/− mouse colon tissue and colon cancer cells, the expression of Wnt2b, LRP8 and Dvl1 are significantly decreased, which are all the Wnt/β-catenin complex genes, similar with the result of the selective ERα antagonist treatment [48]. The Estrogen-induced β-catenin activation also depends on the assistant of Wnt3a and HDAC signaling pathways, which promotes the nuclear localization of β-catenin and enhance the transcription of β-catenin-regulated genes, including CCND1, c-Myc, and the androgen receptor (AR) [49]. Furthermore, in non-canonical pathway, the treatment of E2 interacts with the receptor of IGF-1 (IGF-1R) and sequentially activates the PI3K/Akt/GSK3β signaling with or without the IGF-1, promoting the stabilization of β-catenin and the transcription of the β-catenin-related genes in Wnt-independent pathway [50]. However, Kang’s research found that as a non-canonical estrogen receptor signaling, estrogen-related receptor gamma (ERRG) is highly expressed in gastric cancer and acts as an antagonizer, which induces the proteosome degradation of β-catenin and inhibits β-catenin-TCF4/LEF1 binding to the targeted genes [51, 52]. So, the estrogen-induced β-catenin regulation is still unclear, requiring further investigation (Fig. 1).

Fig. 1
figure 1

The synthesis and function of estrogen in cell transcriptional regulation. The aromatase expressed in liver, placenta, bone and breast promotes the synthesis of estrone from testosterone with the stimulation of LH and FSH. Then estrone mediate the further synthesis of estradiol including 17α- and 17β-estradiol and finally synthesize estriol by hydroxylation. Sequencely, estrogen alternate the immunological differentiation by two pathways. (1) Canonically, estrogen promotes the transcription of estrogen-target genes by ERα/β activation together with co-factor, including GATA3, c-Jun, CBP, and FOXA1. (2) Non-canonically, estrogen enhances the NF-κB, ERK and β-catenin pathway by GPER activation

Estrogen/estrogen receptor in cancer immunotherapy

It has reported that estrogen sex steroid hormones and its receptor present a comprehensive and various physiological functions in the process of tumor development [13]. The estrogen/ER-targeted endocrine therapy has been the standard therapy in breast cancer treatment, such as selective estrogen receptor modulators and aromatase inhibitors [53]. Meanwhile, the abnormal expression levels of estrogen receptor (ER) are also related to the susceptibility to various cancer and alternate the prognosis of tumor patients, especially those of the breast and endometrium [13, 54]. The estrogen-induced therapeutic outcome is also related to the function of anti-tumor immunity, especially in breast cancer, which is closely related to the expression of ER [55]. Abrahamsson and his colleagues found that the estrogen antagonists, tamoxifen and fulvestrant, inhibit the infiltration of neutrophils, fibroblast as well as M2 macrophage and increase the innate immune response in breast cancer [56]. Furthermore, the research from Márquez-Garbán designed a series of selective ER down-regulators (SERDs) and found that the application of SERDs suppression of myeloid-derived suppressor cells (MDSC) and synergistically increased the therapeutic effect of immune checkpoint inhibitors [57]. In this regard, it has a huge amount of potential in the combination between SERDs and immunotherapy. However, it variates in different patients because of the diversity of cancer types. Finding the specific regulation pathway to tumor immune response becomes the importance for the cancer immunotherapy.

Cancer cell

Immune check point

The expression of programmed death ligand-1 (PD-L1) on the surface of tumor cells interacts with its receptor in T cell, Programmed Death-1 (PD-1) and causes the dysfunction of T cell in tumor tissue, which inhibits the T cell-induced anti-tumor immunity. In eutopic epithelial cells, Wu’s research revealed that 17β-estradiol enhances the expression of PD-L1 in a dose-dependent manner [58]. In cancer cells, meanwhile, the bio-information data and cell lines researches showed that the expression level of PD-L1 in ERα+ breast cancer is inferior to the ERα breast cancer [59, 60]. The clinical data showed that female is a disadvantage factor in PD-1-induced melanoma therapy, indicating that the sex hormone from female has the key function in PD-1/PD-L1 axis regulation [61]. The Next Generation Sequencing (NGS) results confirmed that the treatment of E2 is involved in the transcription of PD-L1 in MCF-7 cell line, indicating the negative regulation of PD-L1 induced by estrogen in transcriptional level [62, 63]. The research reported that high level expression of ER enhances the expression of IL-17E, while the expression of IL-17A, IL-17C, and IL-17F is significantly inhibited. IL-17E acted as an antagonist of IL-17 pathway by suppressing the activation function of IL-17A, IL-17C, and IL-17F. The inhibition of ER-induced IL-17 signaling decreases the expression level of PD-L1 in ER+ breast cancer, which reveals the essential role of IL-17 in ER-induced PD-L1 expression decrease [64].

GPER signaling was reported the cross-talk with PD-L1, which contributes to the suppression of tumor immune escape [65, 66]. The treatment of GPER agonist G-1 decreases the cell proliferation of melanoma and suppresses the expression of PD-L1. Also, the combined therapies of anti-PD-1 antibody and G-1 effectively retard the process of melanoma [65]. The similar results also exist in pancreatic ductal adenocarcinoma treatment, which further showed that the G-1-induced inhibition of PD-L1 relies on the phosphorylation of RB (p-RB) and the expression of c-Myc [67]. It seems that NF-κB is the key regulatory pathway in GPER-induced PD-L1 down-regulation. The evidence indicated that NF-κB is decayed after the interaction between GPER and E2 [34]. The inactivation of NF-κB inhibits the expression of COP9 Signalosome Subunit 5 (CSN5), which can be reversed by GPER. CSN5 plays a critical role in the ubiquitination adjustment of PD-L1 and the down-regulation of CSN5 enhances the poly-ubiquitination of PD-L1 and promotes the degradation via ubiquitination pathway [35, 68].

However, the contradictory result from Yang’s research comes out that E2-induced PI3K/Akt pathway activation promotes the expression of PD-L1 by post-transcriptional control and inhibits the anti-tumor function of T cell in ER+ breast cancer [69]. On the other hand, the estrogen-induced ERK activation is also related to the expression alternation of PD-L1. The study found the mutual upregulation of PD-L1 and Bcl-2-associated athanogene-1 (BAG-1) via ERK signaling and caused the resistance of tyrosine kinase inhibitor (TKI) [70]. In addition, the chemotherapeutic treatments of esophageal squamous cell promote the phosphorylation of ERK, consequently enhancing the expression level of PD-L1 and responding for tumor metastasis [71]. As the agonist of ERK, the stimulation of E2 may promote the expression level of PD-L1 via ERK pathway in ER-positive breast cancer. These results suggested that estrogen can also enhance the expression of PD-L1, which is different from the previous research we have discussed before. So, to illuminate the specific function of E2/ER in PD-L1 regulation, the further researches are urgently required.

Cancer stem cell

Cancer stem cells (CSCs) are one of special cancer cell subtypes, which have the ability to self-renew and differentiate to heterogeneous tumor cells [72]. The heterogeneity of CSCs causes the alternation of antigen on the surface of tumor cells and prevents the T cell-induced surveillance [73]. On the other hand, CSCs express high level of PD-L1, IDO1 and enhance the secretion of inhibitory chemokines, including IL-8, CCL2 and CCL5, which are related to the deplete of T cell and Treg differentiation [74, 75]. Uchiumi’s study found that the ER+ breast cancer cells express higher populations of CD44+/CD24, revealing the high level of CSCs retaining ability. On the contrary, ER basal-like breast cancer cells showed the lower stemness in terms of the decrease of ALDH activity [76]. Meanwhile, the surface plasmon resonance test also illuminated that the treatment of estradiol promotes the migration of CSCs and facilitates the metastasis in colorectal cancer [77]. The research proved that the ER-induced DLL1 expression is the key factor in CSCs differentiation. In the ER+ luminal breast cancer, estrogen stabilizes the DLL1-induced Notch signaling activation and controls the function of CSCs. The knock-down of DLL1 reduces the expression of CD24 and CD44, which is the biomarker of breast cancer CSCs, and down-regulates both tumor growth and lung metastasis of luminal breast cancer [78]. Meanwhile, ERα and ERβ exhibit elevated expression of FGF and EGF in CSCs culture and the treatment of estrogen also promotes the expression of CSCs markers in a time-and dose-dependent manner in thyroid cancer, showing the estrogen-induced CSCs differentiation in growth factor-dependent manner [79]. However, Domenici and his colleagues found that ERα inhibits the SOX-2 and SOX-9, which are the biomarkers of CSCs in breast cancer, suggesting the complexity of estrogen-induced CSCs transforming [80]. Meanwhile, the similar results in osteosarcoma elucidate that decitabine promotes the expression of ERα induced by the decrease of DNA methylation and suppresses the biomarker of CSCs, including SOX2, OCT4, and NANOG [81]. This contradictory reveals the complicated regulation of estrogen/ER pathway to CSCs differentiation.

T cell

Cytotoxic T lymphocytes (CTLs) are the principal force in anti-tumor immunity, which are regulated by heterogeneous phenotypes of helper T lymphocytes. Estrogen acts an important role in T cell development and maturity. Moulton found that the treatment of E2 leads to the drastic thymic atrophy [82]. This process can be reversed by decrease of endogenously produced estrogen after ovariectomy [83]. Meanwhile, E2 causes the down-regulation of thymic T cell number and inhibit the proportion of CD4 and CD8 double-positive T cells, while the level of CD4 or CD8 single-positive T cells and CD4CD8CD25CD44+ T cells increase. The alternation of T cells maturity causes the inhibition of T cell dependent inflammation [84]. However, Adori and his colleagues found that estrogen regulates B and T cells by the activation of ERK and AKT phosphorylation, cell-specific Ca2+ signal, and NF-κB pathway, which enhance the T cell-dependent immune response, suggesting the diversity of estrogen-induced regulation in T cells [85].

Estrogen also adjusts the T cell differentiation in the tumor-infiltrating lymphocytes in tumor tissue. T regulatory cells (Treg) (CD4+ FoxP3+) and T helper (CD4+ FoxP3) is significantly increased in ER mutant breast cancer, while CTLs had no difference, indicating the correction between ER and Treg differentiation [86]. With the stimulation of 17β-estradiol, ERβ promotes the differentiation of Treg, which dominates the secretion of IL-10 as well as TGF-beta and down-regulate the activity of CD8+ T cell, causing the suppression of T cell-induced tumor immunocytotoxicity [87, 88]. Garnier and his colleagues found that the E2-induced Treg differentiation in pregnancy-level concentrations also suppresses the differentiation of Th17 cells by the adjustment of PD-1/PD-L1 axis, which is elevated expressed on CD4+ T cells with the treatment of E2 [89, 90]. Moreover, the E2 also inhibits the function of antigen presenting cells (APC) and up-regulates the Treg activity assisted by bone marrow-derived dendritic cells [91]. However, the research also revealed that estrogen-induced Treg activation only existed in high level of estrogen. However, the result totally reversed in low estrogen level [92]. The similar result also showed that the differentiation of Th1 cells enhanced in low estrogen level, which promoted the Th1-induced CTL activation and up-regulated the anti-tumor immunity, while the high level of estrogen increased the proportion of Th2 phenotype, causing the immunity inhibition [58]. In this regard, estrogen indicated the bidirectional function in Treg differentiation, which has the different regulation in cancer immunity in a dose-dependent manner.

Tumor-associated macrophage

As the essential regulator in tumor immunity, macrophages have disparate differentiation, which can generally be separated into two phenotypes: M1 and M2 macrophages [93]. Blood monocytes or tissue-resident macrophages are recruited and functional reprogrammed induced by multiple chemokines secretion, including CCL2, CCL5, C5a, CSF-1, VEGF and IL-34 [94]. The macrophages in tumor tissues, also called TAMs, constitutes the dominant component of the infiltrating leukocyte in all tumor, which are mainly differentiated into M2 phenotype [95]. TAMs are canonically associated with the immunosuppression by following points: (1) TAMs express high level of IDO1 and suppress the activation and proliferation of CD4+ and CD8+ T cells and promote the immunosuppression function of Treg through kynurenine pathway [96]. (2) TAMs secret the immunosuppression cytokines regulate the T cell-induced ant-tumor immunity, including IL-10, IL-6, PGE2, and TGF-beta1 [97]. (3) TAMs express PD-L1 and PD-L2 and participate exhaustion of CD8+ T cell by cell–cell interaction[98, 99].

Estrogen close ties to the polarization and function of macrophage, which has been widely researched in osteoporosis studies. Dou’s researches showed that the proportion of M1 increases in ovariectomized mice and the activation of ERα reduces the M1/M2 ratio by ERα selective agonist 4,4′,4″-(4-propyl-[1H]‐pyrazole-1,3,5-triyl) trisphenol (PPT) [100]. The loss of ERα in macrophages increases the expression of NOS2 and reduces the Arg1 expression, which indicated the M1 macrophages activation [101]. Jing and his colleagues reported that ERα in macrophages promotes the expression of chemokine (C–C motif) ligand 18 (CCL18) and accelerates the mTOR/KIF5B-induced EMT of endometrial cancer and cancer immune escape [102, 103]. Meanwhile, Côté’s study exhibited that GPER1 is also involved in the shift of macrophages toward M2 phenotype together with ERα by depleting the mobilization of NF-κB and iNOS pathway, also showing the participation of GPER in macrophages polarization [104]. The regulation of E2-induced M2 macrophages transformation in the cancer immunity mainly derived from the alternation of cytokine microenvironment. The ERα enhanced the secretion of pro-inflammatory cytokine by down-regulation the PI3K and Akt pathway activation, stimulating the TLR ligand in the surface of macrophages [105]. In response to TLR4 signaling in macrophages, the E2 mediated the secretion of inflammatory cytokine (IL-1β, IL-6, and TNF-α) and contributed to the tumor-associated inflammation and cancer immune escape [106, 107]. Overall, these findings suggested that estrogen decreases the M1 subtype and facilitates the M2 polarization of TAM, which is related to the suppression in anti-cancer immunity.

Cancer-associated fibroblast

Similar with the macrophages, the fibroblasts in tumor tissue, CAFs, are also able to alternate anti-tumor immune. In the innate immunity, CAFs can escape from radiotherapy and suppress the function of Natural Killer (NK) cells by producing PGE2, IDO, TGF-β and other immunosuppressant compounds [108, 109]. Furthermore, CAFs aggravate the glucose deficiency in the milieu and inhibit the migration of cytotoxic T lymphocytes (CTLs) in adaptive immunity [110]. The expression of PD-L1 in CAFs also causes the depletion of CTLs and down-regulates the anti-tumor immunity [111]. By the expression of B7H3, CD73, and DPP4, CAFs maintain the differentiation of Treg and enhance the inhibition T cell proliferation [112]. Taken together, the proportion of CAFs in the tumor tissue is a foretaste of repression of cancer immunity.

The researches have elucidated that CAFs are related to the resistance of tamoxifen-induced endocrine therapy, indicating the relationship between CAFs and estrogen pathway [113]. The main estrogen receptor in breast CAFs is GPER. The activation of GPER by G-1, E2 or 4-hydroxytamoxifen (OHT) promotes the expression of vascular endothelial growth factor (VEGF), connective tissue growth factor (CTGF), c-fos, Cyr61, EGR1 and regulates the adhesion/spreading, proliferation and migration of CAFs in rapid and slow manner in breast cancer [114, 115]. The GPER-mediated CAFs proliferation results from the expression enhancement of FGFR1, which up-regulates the sensitivity of FGF2 and promotes the progression of breast cancer by paracrine manner [116]. CAFs up-regulate the secretion of serval growth factor with the treatment of estrogen, including E2, IL-1β1, VEGF and so on [117, 118]. These factors facilitate the EMT of breast cancer by hypoxia, COX-2 and ABCG2 transcription and facilitate the immunity escape [118, 119]. Moreover, estrogen promotes the secretion of IL-6 derived from CAFs, which acts as the immunosuppression cytokine and inhibit the cancer immunity [120, 121]. These findings suggested that E2 and ER is a critical regulator in CAFs-induced immune escape.

Cytokines and chemokines

The interaction between cancer cells and immunity induced by cytokines and chemokines plays an important role in cancer initiation, development and therapeutic effect [122]. The researches have elucidated the E2-induced inflammatory cytokines secretion in tumor and immune cells, revealing another E2/ER-induced regulatory pathway in cancer immunity. The activation of ERβ by LY500307 promotes the secretion of IL-1β and enhance the infiltration of neutrophils in cancer tissue, which inhibits the tumor progress and lung metastasis [123]. Recent research found that the enhancement of estrogen facilitates the secretion of pro-tumor cytokines from Treg, Th2, CAFs and other immunosuppressive cells, including IL-4, IL-6, TNFα, and IL-17A while decrease the expression of anti-tumor cytokines from M1, NK, CD8+ T cells and Th1 cells, including IL-12 and IFNγ [124]. These estrogen-induced secretion pattern causes the M2 shifting and dominate the immunosuppression in TME. Taking tagether, these results reveal that E2/ER has the diversity effects on the cancer immunity which is according to the target cell types.

On the other hand, the expression of ER is related to the secretion of chemokines, which acts as the bridge between cancer cells and immune cells. The estrogen and ERα expression enhances the secretion of CCL2 and increases the expression level of macrophage-induced C-X-C Motif Chemokine Ligand 12 (CXCL12) [125, 126]. Meanwhile, ERα can also promote the CXCL11 secretion of cancer cells and activate EMT induced by CXCR7 [127]. The secretion of CCL2 and CXCL cytokine subfamily cause the infiltration and M2 conversion of macrophages in the cancer niche, leading to the immune escape and long-distance metastasis. In this regard, these researches indicated that the E2/ER-induced cytokines and chemokines secretion in different cellular compartments of TME can be the effective therapeutic target to optimize the cancer immunotherapy efficacy.

Collagen and tumor stroma

The diversity of biology structural and biological functions attribute to the expression of collagen, which is the tissue and molecular scaffold of animal life [128]. The collagen is the dominating composition in cancer tissue, which is composed of the tumor stroma, providing the mechanical support to the cancer cells. The biosynthesis of collagen is manipulated by the TME, including secretion of TGF-β [129], FGF [130] and estrogen [131]. Collagen has the key function in anti-tumor immunity regulation, together with macrophages, lymphocytes, and fibroblasts [132]. The expression of collagen mediates the dysfunction of CD8+ T cell in LAIR1-dependent manner and depleting the LOXL2, the key factors in collagen synthesis process, reverses the suppression of T cell infiltration [133]. These results suggested the importance of collagen in cancer immunity regulation.

As an essential factor in collagen regulation, ERα promotes the transcription of miR-1271 in T47D and MCF-7 and regulates the expression of TGF-β, which is the essential cytokine in collagenous fiber synthesis and manipulates the alternation of cancer tissue fibrosis and immunity [134, 135]. The research revealed that collagen can be the biomarker of breast density, which has a positive correction with ERβ2 expression in breast cancer [55]. Huo and his colleagues also found that collagen expresses elevated in high mammographic density (LMD) breast tissues together with the significantly overexpression of aromatase, which revealed the highly production of estrogen. However, the expression of ERα and ERβ present no difference in LMD, suggesting the secretion of collagen is related to the stimulation of estrogen rather than the up-regulation of ERβ [136]. The specific mechanism of E2/ER-induced collagen synthesis in cancer tissues is possibly related to the MAPK pathway and the activation of AP-1, which can be blocked by tamoxifen [137]. However, the estrogen-induced tumor collagen synthesis still requires the further confirmed.

One possible reason for the estrogen-induced collagen immunosuppression is that the expression of collagen increases the density of tumor stroma, which reduces the infiltration of lymphocytes and avoids the contact between CTLs and tumor cells. In this process, the expression of stroma ColXα1 has proved the essential role in tumor-infiltrating lymphocytes regulation, which indicated the low overall survival in ER+/HER2+ breast cancer [138, 139]. On the other hand, the densified tumor stroma reduces the oxygen diffusion in tumor tissues and promotes the expression of hypoxia-inducible factor 1α (HIF1α), which induces immune checkpoint marker expression and immunosuppressive cytokines release [55, 140]. Moreover, the accumulation of collagen-I in mammary carcinomas promotes the transformation to CSCs through the activation of AKT-mTOR and YAP pathway and increases the possibility of cancer metastasis [141].

Conclusion and prospection

The estrogen functions as the immune regulator in anti-tumor immunity in diverse pathways. This review mainly summarized the E2-related canonical and non-canonical cell activation signal pathway. Then the estrogen-induced immunologic differentiation in cancer cells was mainly elucidated, such as PD-L1 expression and CSCs regulation. Moreover, the estrogen-induced recruitment and chromatin remodeling of immune-related cells, including T cells, TAMs, CAFs, and the expression of cytokines and chemokines, collagen as well as the tumor stroma, is also discussed. The specific estrogen-induced regulation in cancer and TME was summarized in Fig. 2 and Table 1. In view of the regulatory function in this TME component, several potential combinations of estrogen/ER-target therapy for cancer treatment have been tested in various research, including the immune checkpoint inhibitor therapy [142], immune-modulating therapy [143], and cancer vaccination therapy [144]. Meanwhile, the therapies targeting to the estrogen-induced cytokines secretion, including IL-17, CCL2, FGF, TGF-β, et al. and consequent differentiation of cancer and T cells should also be taken into consideration to reverse the hormone-related cancer immunity depletion. Although it is still facing challenge, the further research in the estrogen-induced immunologic regulation will provide the foundation to illuminate the endocrine-related TME and optimize the immunotherapy in cancer treatment.

Fig. 2
figure 2

The schematic diagram of estrogen-induced anti-tumor immunity regulation. The estrogen-related immunity reugulation including: (1) mediate the expression of PD-L1 and CSCs differentiation; (2) TAMs differentiation and secretion; (3) CAFs proliferation; (4) T cell maturity and Treg regulation; (5) Cytokines and chemokines secretion regulation

Table 1 The regulatory function of estrogen and ER in cancer cell and various TME components

Availability of data and materials

Not applicable.


  1. 1.

    Jaillon S, Berthenet K, Garlanda C. Sexual dimorphism in innate immunity. Clin Rev Allergy Immunol. 2019;56(3):308–21.

    CAS  PubMed  Article  Google Scholar 

  2. 2.

    Li S, Jiang K, Li J, Hao X, Chu W, Luo C, Zhu Y, Xie R, Chen B. Estrogen enhances the proliferation and migration of ovarian cancer cells by activating transient receptor potential channel C3. J Ovarian Res. 2020;13(1):20.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  3. 3.

    Dubois C, Rocks N, Blacher S, Primac I, Gallez A, Garcia-Caballero M, Gerard C, Brouchet L, Noel A, Lenfant F, et al. Lymph/angiogenesis contributes to sex differences in lung cancer through oestrogen receptor alpha signalling. Endocr Relat Cancer. 2019;26(2):201–16.

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    Liu Y, Zhao R, Chi S, Zhang W, Xiao C, Zhou X, Zhao Y, Wang H. UBE2C is upregulated by estrogen and promotes epithelial-mesenchymal transition via p53 in endometrial cancer. Mol Cancer Res. 2020;18(2):204–15.

    CAS  PubMed  Article  Google Scholar 

  5. 5.

    Fuentes N, Silveyra P. Estrogen receptor signaling mechanisms. Adv Protein Chem Struct Biol. 2019;116:135–70.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. 6.

    Schulster M, Bernie AM, Ramasamy R. The role of estradiol in male reproductive function. Asian J Androl. 2016;18(3):435–40.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. 7.

    Parween S, DiNardo G, Baj F, Zhang C, Gilardi G, Pandey AV. Differential effects of variations in human P450 oxidoreductase on the aromatase activity of CYP19A1 polymorphisms R264C and R264H. J Steroid Biochem Mol Biol. 2020;196:105507.

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    Xu H, Zhang X, Ye Y, Li X. Bisphenol A affects estradiol metabolism by targeting CYP1A1 and CYP19A1 in human placental JEG-3 cells. Toxicol In Vitro. 2019;61:104615.

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    Moore SC, Matthews CE, Ou Shu X, Yu K, Gail MH, Xu X, Ji BT, Chow WH, Cai Q, Li H, et al. Endogenous estrogens, estrogen metabolites, and breast cancer risk in postmenopausal Chinese women. J Natl Cancer Inst. 2016.

    Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Luine VN. Estradiol and cognitive function: past, present and future. Horm Behav. 2014;66(4):602–18.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. 11.

    Hamson DK, Roes MM, Galea LA. Sex hormones and cognition: neuroendocrine influences on memory and learning. Compr Physiol. 2016;6(3):1295–337.

    PubMed  Article  Google Scholar 

  12. 12.

    Auchus ML, Auchus RJ. Human steroid biosynthesis for the oncologist. J Investig Med. 2012;60(2):495–503.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. 13.

    Liang J, Shang Y. Estrogen and cancer. Annu Rev Physiol. 2013;75:225–40.

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Kim C, Harlow SD, Zheng H, McConnell DS, Randolph JF Jr. Changes in androstenedione, dehydroepiandrosterone, testosterone, estradiol, and estrone over the menopausal transition. Womens Midlife Health. 2017;3:9.

    PubMed  PubMed Central  Article  Google Scholar 

  15. 15.

    Jensen EV, Jacobson HI, Walf AA, Frye CA. Estrogen action: a historic perspective on the implications of considering alternative approaches. Physiol Behav. 2010;99(2):151–62.

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Cooke PS, Nanjappa MK, Ko C, Prins GS, Hess RA. Estrogens in male physiology. Physiol Rev. 2017;97(3):995–1043.

    PubMed  PubMed Central  Article  Google Scholar 

  17. 17.

    Jia M, Dahlman-Wright K, Gustafsson JA. Estrogen receptor alpha and beta in health and disease. Best Pract Res Clin Endocrinol Metab. 2015;29(4):557–68.

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Zhang Z, Yu W, Tang D, Zhou Y, Bi M, Wang H, Zheng Y, Chen M, Li L, Xu X, et al. Epigenomics-based identification of oestrogen-regulated long noncoding RNAs in ER+ breast cancer. RNA Biol. 2020;17(11):1590–602.

    CAS  PubMed  Article  Google Scholar 

  19. 19.

    Lakshmanan MD, Shaheer K. Endocrine disrupting chemicals may deregulate DNA repair through estrogen receptor mediated seizing of CBP/p300 acetylase. J Endocrinol Invest. 2020;43(9):1189–96.

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Zhu C, Li L, Zhang Z, Bi M, Wang H, Su W, Hernandez K, Liu P, Chen J, Chen M, et al. A non-canonical role of YAP/TEAD Is required for activation of estrogen-regulated enhancers in breast cancer. Mol Cell. 2019;75(4):791-806 e798.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. 21.

    Choi J, Lysakovskaia K, Stik G, Demel C, Soding J, Tian TV, Graf T, Cramer P. Evidence for additive and synergistic action of mammalian enhancers during cell fate determination. Elife. 2021;10:e65381.

    PubMed  PubMed Central  Article  Google Scholar 

  22. 22.

    Li W, Notani D, Ma Q, Tanasa B, Nunez E, Chen AY, Merkurjev D, Zhang J, Ohgi K, Song X, et al. Functional roles of enhancer RNAs for oestrogen-dependent transcriptional activation. Nature. 2013;498(7455):516–20.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23.

    Rahman S, Zorca CE, Traboulsi T, Noutahi E, Krause MR, Mader S, Zenklusen D. Single-cell profiling reveals that eRNA accumulation at enhancer-promoter loops is not required to sustain transcription. Nucleic Acids Res. 2017;45(6):3017–30.

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    Molina L, Figueroa CD, Bhoola KD, Ehrenfeld P. GPER-1/GPR30 a novel estrogen receptor sited in the cell membrane: therapeutic coupling to breast cancer. Expert Opin Ther Targets. 2017;21(8):755–66.

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Revankar CM, Cimino DF, Sklar LA, Arterburn JB, Prossnitz ER. A transmembrane intracellular estrogen receptor mediates rapid cell signaling. Science. 2005;307(5715):1625–30.

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    Toran-Allerand CD. Estrogen and the brain: beyond ER-alpha, ER-beta, and 17beta-estradiol. Ann N Y Acad Sci. 2005;1052:136–44.

    CAS  PubMed  Article  Google Scholar 

  27. 27.

    Toran-Allerand CD, Guan X, MacLusky NJ, Horvath TL, Diano S, Singh M, Connolly ES Jr, Nethrapalli IS, Tinnikov AA. ER-X: a novel, plasma membrane-associated, putative estrogen receptor that is regulated during development and after ischemic brain injury. J Neurosci. 2002;22(19):8391–401.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. 28.

    Fusella F, Secli L, Busso E, Krepelova A, Moiso E, Rocca S, Conti L, Annaratone L, Rubinetto C, Mello-Grand M, et al. The IKK/NF-kappaB signaling pathway requires Morgana to drive breast cancer metastasis. Nat Commun. 2017;8(1):1636.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  29. 29.

    Liu B, Sun L, Liu Q, Gong C, Yao Y, Lv X, Lin L, Yao H, Su F, Li D, et al. A cytoplasmic NF-kappaB interacting long noncoding RNA blocks IkappaB phosphorylation and suppresses breast cancer metastasis. Cancer Cell. 2015;27(3):370–81.

    CAS  PubMed  Article  Google Scholar 

  30. 30.

    Radisky DC, Bissell MJ. NF-kappaB links oestrogen receptor signalling and EMT. Nat Cell Biol. 2007;9(4):361–3.

    CAS  PubMed  Article  Google Scholar 

  31. 31.

    Wang X, Belguise K, Kersual N, Kirsch KH, Mineva ND, Galtier F, Chalbos D, Sonenshein GE. Oestrogen signalling inhibits invasive phenotype by repressing RelB and its target BCL2. Nat Cell Biol. 2007;9(4):470–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. 32.

    Zhu P, Liao LY, Zhao TT, Mo XM, Chen GG, Liu ZM. GPER/ERK&AKT/NF-kappaB pathway is involved in cadmium-induced proliferation, invasion and migration of GPER-positive thyroid cancer cells. Mol Cell Endocrinol. 2017;442:68–80.

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Zhu G, Huang Y, Wu C, Wei D, Shi Y. Activation of G-protein-coupled estrogen receptor inhibits the migration of human nonsmall cell lung cancer cells via IKK-beta/NF-kappaB signals. DNA Cell Biol. 2016;35(8):434–42.

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Liang S, Chen Z, Jiang G, Zhou Y, Liu Q, Su Q, Wei W, Du J, Wang H. Activation of GPER suppresses migration and angiogenesis of triple negative breast cancer via inhibition of NF-kappaB/IL-6 signals. Cancer Lett. 2017;386:12–23.

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Frasor J, Weaver A, Pradhan M, Dai Y, Miller LD, Lin CY, Stanculescu A. Positive cross-talk between estrogen receptor and NF-kappaB in breast cancer. Cancer Res. 2009;69(23):8918–25.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. 36.

    Yang M, Liu B, Jin L, Tao H, Yang Z. Estrogen receptor beta exhibited anti-tumor effects on osteosarcoma cells by regulating integrin, IAP, NF-kB/BCL-2 and PI3K/Akt signal pathway. J Bone Oncol. 2017;9:15–20.

    PubMed  PubMed Central  Article  Google Scholar 

  37. 37.

    Wang J, Guo X, Xie C, Jiang J. KIF15 promotes pancreatic cancer proliferation via the MEK-ERK signalling pathway. Br J Cancer. 2017;117(2):245–55.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. 38.

    Gao J, Fan M, Xiang G, Wang J, Zhang X, Guo W, Wu X, Sun Y, Gu Y, Ge H, et al. Diptoindonesin G promotes ERK-mediated nuclear translocation of p-STAT1 (Ser727) and cell differentiation in AML cells. Cell Death Dis. 2017;8(5):e2765.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. 39.

    Sun Y, Lan M, Chen X, Dai Y, Zhao X, Wang L, Zhao T, Li Y, Zhu J, Zhang X, et al. Anti-invasion and anti-metastasis effects of Valjatrate E via reduction of matrix metalloproteinases expression and suppression of MAPK/ERK signaling pathway. Biomed Pharmacother. 2018;104:817–24.

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Guo YJ, Pan WW, Liu SB, Shen ZF, Xu Y, Hu LL. ERK/MAPK signalling pathway and tumorigenesis. Exp Ther Med. 2020;19(3):1997–2007.

    PubMed  PubMed Central  Google Scholar 

  41. 41.

    Zhang XT, Kang LG, Ding L, Vranic S, Gatalica Z, Wang ZY. A positive feedback loop of ER-alpha36/EGFR promotes malignant growth of ER-negative breast cancer cells. Oncogene. 2011;30(7):770–80.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  42. 42.

    Sun Q, Liang Y, Zhang T, Wang K, Yang X. ER-alpha36 mediates estrogen-stimulated MAPK/ERK activation and regulates migration, invasion, proliferation in cervical cancer cells. Biochem Biophys Res Commun. 2017;487(3):625–32.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  43. 43.

    Pollard KJ, Daniel JM. Nuclear estrogen receptor activation by insulin-like growth factor-1 in Neuro-2A neuroblastoma cells requires endogenous estrogen synthesis and is mediated by mutually repressive MAPK and PI3K cascades. Mol Cell Endocrinol. 2019;490:68–79.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. 44.

    Sathya S, Sudhagar S, Lakshmi BS. Estrogen suppresses breast cancer proliferation through GPER / p38 MAPK axis during hypoxia. Mol Cell Endocrinol. 2015;417:200–10.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  45. 45.

    Thakur R, Mishra DP. Pharmacological modulation of beta-catenin and its applications in cancer therapy. J Cell Mol Med. 2013;17(4):449–56.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. 46.

    Zhan T, Rindtorff N, Boutros M. Wnt signaling in cancer. Oncogene. 2017;36(11):1461–73.

    CAS  PubMed  Article  Google Scholar 

  47. 47.

    Guo Y, Li B, Yan X, Shen X, Ma J, Liu S, Zhang D. Bisphenol A and polychlorinated biphenyls enhance the cancer stem cell properties of human ovarian cancer cells by activating the WNT signaling pathway. Chemosphere. 2020;246:125775.

    CAS  PubMed  Article  Google Scholar 

  48. 48.

    Liu S, Fan W, Gao X, Huang K, Ding C, Ma G, Yan L, Song S. Estrogen receptor alpha regulates the Wnt/beta-catenin signaling pathway in colon cancer by targeting the NOD-like receptors. Cell Signal. 2019;61:86–92.

    CAS  PubMed  Article  Google Scholar 

  49. 49.

    Ali M, Shahin SM, Sabri NA, Al-Hendy A, Yang Q. Activation of beta-catenin signaling and its crosstalk with estrogen and histone deacetylases in human uterine fibroids. J Clin Endocrinol Metab. 2020;105(4):e1517–35.

    Article  Google Scholar 

  50. 50.

    Scott EL, Brann DW. Estrogen regulation of Dkk1 and Wnt/beta-Catenin signaling in neurodegenerative disease. Brain Res. 2013;1514:63–74.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  51. 51.

    Kang MH, Choi H, Oshima M, Cheong JH, Kim S, Lee JH, Park YS, Choi HS, Kweon MN, Pack CG, et al. Estrogen-related receptor gamma functions as a tumor suppressor in gastric cancer. Nat Commun. 2018;9(1):1920.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  52. 52.

    Ranganathan P, Nadig N, Nambiar S. Non-canonical estrogen signaling in endocrine resistance. Front Endocrinol (Lausanne). 2019;10:708.

    Article  Google Scholar 

  53. 53.

    Shagufta, Ahmad I, Mathew S, Rahman S. Recent progress in selective estrogen receptor downregulators (SERDs) for the treatment of breast cancer. RSC Med Chem. 2020;11(4):438–54.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. 54.

    Bartels S, Christgen M, Luft A, Persing S, Jodecke K, Lehmann U, Kreipe H. Estrogen receptor (ESR1) mutation in bone metastases from breast cancer. Mod Pathol. 2018;31(1):56–61.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  55. 55.

    Huang B, Omoto Y, Iwase H, Yamashita H, Toyama T, Coombes RC, Filipovic A, Warner M, Gustafsson JA. Differential expression of estrogen receptor alpha, beta1, and beta2 in lobular and ductal breast cancer. Proc Natl Acad Sci U S A. 2014;111(5):1933–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. 56.

    Abrahamsson A, Rodriguez GV, Dabrosin C. Fulvestrant-mediated attenuation of the innate immune response decreases ER(+) breast cancer growth in vivo more effectively than tamoxifen. Cancer Res. 2020;80(20):4487–99.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  57. 57.

    Marquez-Garban DC, Deng G, Comin-Anduix B, Garcia AJ, Xing Y, Chen HW, Cheung-Lau G, Hamilton N, Jung ME, Pietras RJ. Antiestrogens in combination with immune checkpoint inhibitors in breast cancer immunotherapy. J Steroid Biochem Mol Biol. 2019;193:10415.

    Article  CAS  Google Scholar 

  58. 58.

    Salem ML. Estrogen, a double-edged sword: modulation of TH1- and TH2-mediated inflammations by differential regulation of TH1/TH2 cytokine production. Curr Drug Targets Inflamm Allergy. 2004;3(1):97–104.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  59. 59.

    Sobral-Leite M, Van de Vijver K, Michaut M, van der Linden R, Hooijer GKJ, Horlings HM, Severson TM, Mulligan AM, Weerasooriya N, Sanders J, et al. Assessment of PD-L1 expression across breast cancer molecular subtypes, in relation to mutation rate, BRCA1-like status, tumor-infiltrating immune cells and survival. Oncoimmunology. 2018;7(12):e1509820.

    PubMed  PubMed Central  Article  Google Scholar 

  60. 60.

    Romero Y, Wise R, Zolkiewska A. Proteolytic processing of PD-L1 by ADAM proteases in breast cancer cells. Cancer Immunol Immunother. 2020;69(1):43–55.

    CAS  PubMed  Article  Google Scholar 

  61. 61.

    Nosrati A, Tsai KK, Goldinger SM, Tumeh P, Grimes B, Loo K, Algazi AP, Nguyen-Kim TDL, Levesque M, Dummer R, et al. Evaluation of clinicopathological factors in PD-1 response: derivation and validation of a prediction scale for response to PD-1 monotherapy. Br J Cancer. 2017;116(9):1141–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. 62.

    Liu L, Shen Y, Zhu X, Lv R, Li S, Zhang Z, Shi YG, Tan L. ERalpha is a negative regulator of PD-L1 gene transcription in breast cancer. Biochem Biophys Res Commun. 2018;505(1):157–61.

    CAS  PubMed  Article  Google Scholar 

  63. 63.

    Kosvyra A, Maramis C, Chouvarda I. Developing an integrated genomic profile for cancer patients with the use of NGS data. Emerg Sci J. 2019;3(3):157–67.

    Article  Google Scholar 

  64. 64.

    Shuai C, Yang X, Pan H, Han W. Estrogen receptor downregulates expression of PD-1/PD-L1 and infiltration of CD8(+) T cells by inhibiting IL-17 signaling transduction in breast cancer. Front Oncol. 2020;10:582863.

    PubMed  PubMed Central  Article  Google Scholar 

  65. 65.

    Natale CA, Li J, Zhang J, Dahal A, Dentchev T, Stanger BZ, Ridky TW. Activation of G protein-coupled estrogen receptor signaling inhibits melanoma and improves response to immune checkpoint blockade. Elife. 2018;7:e31770.

    PubMed  PubMed Central  Article  Google Scholar 

  66. 66.

    Cerezo M, Guemiri R, Druillennec S, Girault I, Malka-Mahieu H, Shen S, Allard D, Martineau S, Welsch C, Agoussi S, et al. Translational control of tumor immune escape via the eIF4F-STAT1-PD-L1 axis in melanoma. Nat Med. 2018;24(12):1877–86.

    CAS  PubMed  Article  Google Scholar 

  67. 67.

    Natale CA, Li J, Pitarresi JR, Norgard RJ, Dentchev T, Capell BC, Seykora JT, Stanger BZ, Ridky TW. Pharmacologic activation of the G protein-coupled estrogen receptor inhibits pancreatic ductal adenocarcinoma. Cell Mol Gastroenterol Hepatol. 2020;10(4):868-880 e861.

    PubMed  PubMed Central  Article  Google Scholar 

  68. 68.

    Lim SO, Li CW, Xia W, Cha JH, Chan LC, Wu Y, Chang SS, Lin WC, Hsu JM, Hsu YH, et al. Deubiquitination and stabilization of PD-L1 by CSN5. Cancer Cell. 2016;30(6):925–39.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. 69.

    Yang L, Huang F, Mei J, Wang X, Zhang Q, Wang H, Xi M, You Z. Posttranscriptional control of PD-L1 expression by 17beta-estradiol via PI3K/Akt signaling pathway in ERalpha-positive cancer cell lines. Int J Gynecol Cancer. 2017;27(2):196–205.

    PubMed  PubMed Central  Article  Google Scholar 

  70. 70.

    Lin PL, Wu TC, Wu DW, Wang L, Chen CY, Lee H. An increase in BAG-1 by PD-L1 confers resistance to tyrosine kinase inhibitor in non-small cell lung cancer via persistent activation of ERK signalling. Eur J Cancer. 2017;85:95–105.

    CAS  PubMed  Article  Google Scholar 

  71. 71.

    Ng HY, Li J, Tao L, Lam AK, Chan KW, Ko JMY, Yu VZ, Wong M, Li B, Lung ML. Chemotherapeutic treatments increase PD-L1 expression in esophageal squamous cell carcinoma through EGFR/ERK activation. Transl Oncol. 2018;11(6):1323–33.

    PubMed  PubMed Central  Article  Google Scholar 

  72. 72.

    Prasetyanti PR, Medema JP. Intra-tumor heterogeneity from a cancer stem cell perspective. Mol Cancer. 2017;16(1):41.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  73. 73.

    Lorenzo-Sanz L, Munoz P. Tumor-infiltrating immunosuppressive cells in cancer-cell plasticity, tumor progression and therapy response. Cancer Microenviron. 2019;12(2–3):119–32.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  74. 74.

    Hsu JM, Xia W, Hsu YH, Chan LC, Yu WH, Cha JH, Chen CT, Liao HW, Kuo CW, Khoo KH, et al. STT3-dependent PD-L1 accumulation on cancer stem cells promotes immune evasion. Nat Commun. 2018;9(1):1908.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  75. 75.

    Low HY, Lee YC, Lee YJ, Wang HL, Chen YI, Chien PJ, Li ST, Chang WW. Reciprocal regulation between indoleamine 2,3-dioxigenase 1 and notch1 involved in radiation response of cervical cancer stem cells. Cancers (Basel). 2020;12(6):1547.

    CAS  Article  Google Scholar 

  76. 76.

    Uchiumi K, Tsuboi K, Sato N, Ito T, Hirakawa H, Niwa T, Yamaguchi Y, Hayashi SI. Cancer stem-like properties of hormonal therapy-resistant breast cancer cells. Breast Cancer. 2019;26(4):459–70.

    PubMed  Article  Google Scholar 

  77. 77.

    Zamani ARN, Avci CB, Ahmadi M, Pouyafar A, Bagheri HS, Fathi F, Heidarzadeh M, Rezaie J, Mirhosseini Y, Saberianpour S, et al. Estradiol modulated colorectal cancer stem cells bioactivity and interaction with endothelial cells. Life Sci. 2020;257:118078.

    CAS  PubMed  Article  Google Scholar 

  78. 78.

    Kumar S, Srivastav RK, Wilkes DW, Ross T, Kim S, Kowalski J, Chatla S, Zhang Q, Nayak A, Guha M, et al. Estrogen-dependent DLL1-mediated Notch signaling promotes luminal breast cancer. Oncogene. 2019;38(12):2092–107.

    CAS  PubMed  Article  Google Scholar 

  79. 79.

    Zane M, Parello C, Pennelli G, Townsend DM, Merigliano S, Boscaro M, Toniato A, Baggio G, Pelizzo MR, Rubello D, et al. Estrogen and thyroid cancer is a stem affair: a preliminary study. Biomed Pharmacother. 2017;85:399–411.

    CAS  PubMed  Article  Google Scholar 

  80. 80.

    Domenici G, Aurrekoetxea-Rodriguez I, Simoes BM, Rabano M, Lee SY, Millan JS, Comaills V, Oliemuller E, Lopez-Ruiz JA, Zabalza I, et al. A Sox2-Sox9 signalling axis maintains human breast luminal progenitor and breast cancer stem cells. Oncogene. 2019;38(17):3151–69.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. 81.

    Lillo Osuna MA, Garcia-Lopez J, El Ayachi I, Fatima I, Khalid AB, Kumpati J, Slayden AV, Seagroves TN, Miranda-Carboni GA, Krum SA. Activation of estrogen receptor alpha by decitabine inhibits osteosarcoma growth and metastasis. Cancer Res. 2019;79(6):1054–68.

    PubMed  Article  Google Scholar 

  82. 82.

    Moulton VR. Sex hormones in acquired immunity and autoimmune disease. Front Immunol. 2018;9:2279.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  83. 83.

    Cepeda S, Griffith AV. Thymic stromal cells: roles in atrophy and age-associated dysfunction of the thymus. Exp Gerontol. 2018;105:113–7.

    CAS  PubMed  Article  Google Scholar 

  84. 84.

    Bernardi AI, Andersson A, Stubelius A, Grahnemo L, Carlsten H, Islander U. Selective estrogen receptor modulators in T cell development and T cell dependent inflammation. Immunobiology. 2015;220(10):1122–8.

    CAS  PubMed  Article  Google Scholar 

  85. 85.

    Adori M, Kiss E, Barad Z, Barabas K, Kiszely E, Schneider A, Kovesdi D, Sziksz E, Abraham IM, Matko J, et al. Estrogen augments the T cell-dependent but not the T-independent immune response. Cell Mol Life Sci. 2010;67(10):1661–74.

    CAS  PubMed  Article  Google Scholar 

  86. 86.

    Williams MM, Spoelstra NS, Arnesen S, O’Neill KI, Christenson JL, Reese J, Torkko KC, Goodspeed A, Rosas E, Hanamura T, et al. Steroid hormone receptor and infiltrating immune cell status reveals therapeutic vulnerabilities of esr1-mutant breast cancer. Cancer Res. 2021;81(3):732–46.

    CAS  PubMed  Article  Google Scholar 

  87. 87.

    Guo D, Liu X, Zeng C, Cheng L, Song G, Hou X, Zhu L, Zou K. Estrogen receptor beta activation ameliorates DSS-induced chronic colitis by inhibiting inflammation and promoting Treg differentiation. Int Immunopharmacol. 2019;77:105971.

    CAS  PubMed  Article  Google Scholar 

  88. 88.

    Jarnicki AG, Lysaght J, Todryk S, Mills KH. Suppression of antitumor immunity by IL-10 and TGF-beta-producing T cells infiltrating the growing tumor: influence of tumor environment on the induction of CD4+ and CD8+ regulatory T cells. J Immunol. 2006;177(2):896–904.

    CAS  PubMed  Article  Google Scholar 

  89. 89.

    Polanczyk MJ, Hopke C, Vandenbark AA, Offner H. Treg suppressive activity involves estrogen-dependent expression of programmed death-1 (PD-1). Int Immunol. 2007;19(3):337–43.

    CAS  PubMed  Article  Google Scholar 

  90. 90.

    Garnier L, Laffont S, Lelu K, Yogev N, Waisman A, Guery JC. Estrogen signaling in bystander Foxp3(neg) CD4(+) T cells suppresses cognate Th17 differentiation in trans and protects from central nervous system autoimmunity. J Immunol. 2018;201(11):3218–28.

    CAS  PubMed  Article  Google Scholar 

  91. 91.

    Polanczyk MJ, Hopke C, Vandenbark AA, Offner H. Estrogen-mediated immunomodulation involves reduced activation of effector T cells, potentiation of Treg cells, and enhanced expression of the PD-1 costimulatory pathway. J Neurosci Res. 2006;84(2):370–8.

    CAS  PubMed  Article  Google Scholar 

  92. 92.

    Tulchiner G, Pichler R, Ulmer H, Staudacher N, Lindner AK, Brunner A, Zelger B, Steinkohl F, Aigner F, Horninger W, et al. Sex-specific hormone changes during immunotherapy and its influence on survival in metastatic renal cell carcinoma. Cancer Immunol Immunother. 2021.

    Article  PubMed  Google Scholar 

  93. 93.

    Zhang Y, Yu G, Chu H, Wang X, Xiong L, Cai G, Liu R, Gao H, Tao B, Li W, et al. Macrophage-associated PGK1 phosphorylation promotes aerobic glycolysis and tumorigenesis. Mol Cell. 2018;71(2):201-215 e207.

    CAS  PubMed  Article  Google Scholar 

  94. 94.

    Mantovani A, Marchesi F, Malesci A, Laghi L, Allavena P. Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol. 2017;14(7):399–416.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  95. 95.

    Wang J, Bao Y, Yao Y. Application of bionanomaterials in tumor immune microenvironment therapy. J Immunol Res. 2021;2021:6663035.

    PubMed  PubMed Central  Google Scholar 

  96. 96.

    Munn DH, Mellor AL. Indoleamine 2,3 dioxygenase and metabolic control of immune responses. Trends Immunol. 2013;34(3):137–43.

    CAS  PubMed  Article  Google Scholar 

  97. 97.

    Zimmermann W, Kammerer R. The immune-modulating pregnancy-specific glycoproteins evolve rapidly and their presence correlates with hemochorial placentation in primates. BMC Genomics. 2021;22(1):128.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  98. 98.

    Roux C, Jafari SM, Shinde R, Duncan G, Cescon DW, Silvester J, Chu MF, Hodgson K, Berger T, Wakeham A, et al. Reactive oxygen species modulate macrophage immunosuppressive phenotype through the up-regulation of PD-L1. Proc Natl Acad Sci U S A. 2019;116(10):4326–35.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  99. 99.

    Tavukcuoglu E, Horzum U, Yilmaz KB, Esendagli G. PD-L2(+) wound zone macrophage-like cells display M1/M2-mixed activation and restrain the effector Th1 responses. Immunol Cell Biol. 2020;98(2):152–64.

    CAS  PubMed  Article  Google Scholar 

  100. 100.

    Dou C, Ding N, Zhao C, Hou T, Kang F, Cao Z, Liu C, Bai Y, Dai Q, Ma Q, et al. Estrogen deficiency-mediated M2 macrophage osteoclastogenesis contributes to M1/M2 ratio alteration in ovariectomized osteoporotic mice. J Bone Miner Res. 2018;33(5):899–908.

    CAS  PubMed  Article  Google Scholar 

  101. 101.

    Campbell L, Emmerson E, Williams H, Saville CR, Krust A, Chambon P, Mace KA, Hardman MJ. Estrogen receptor-alpha promotes alternative macrophage activation during cutaneous repair. J Invest Dermatol. 2014;134(9):2447–57.

    CAS  PubMed  Article  Google Scholar 

  102. 102.

    Jing X, Peng J, Dou Y, Sun J, Ma C, Wang Q, Zhang L, Luo X, Kong B, Zhang Y, et al. Macrophage ERalpha promoted invasion of endometrial cancer cell by mTOR/KIF5B-mediated epithelial to mesenchymal transition. Immunol Cell Biol. 2019;97(6):563–76.

    CAS  PubMed  Article  Google Scholar 

  103. 103.

    Jiang Y, Zhan H. Communication between EMT and PD-L1 signaling: new insights into tumor immune evasion. Cancer Lett. 2020;468:72–81.

    CAS  PubMed  Article  Google Scholar 

  104. 104.

    Cote M, Bourque M, Poirier AA, Aube B, Morissette M, Di Paolo T, Soulet D. GPER1-mediated immunomodulation and neuroprotection in the myenteric plexus of a mouse model of Parkinson’s disease. Neurobiol Dis. 2015;82:99–113.

    CAS  PubMed  Article  Google Scholar 

  105. 105.

    Kovats S. Estrogen receptors regulate innate immune cells and signaling pathways. Cell Immunol. 2015;294(2):63–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  106. 106.

    Balkwill F. Tumour necrosis factor and cancer. Nat Rev Cancer. 2009;9(5):361–71.

    CAS  PubMed  Article  Google Scholar 

  107. 107.

    Calippe B, Douin-Echinard V, Delpy L, Laffargue M, Lelu K, Krust A, Pipy B, Bayard F, Arnal JF, Guery JC, et al. 17Beta-estradiol promotes TLR4-triggered proinflammatory mediator production through direct estrogen receptor alpha signaling in macrophages in vivo. J Immunol. 2010;185(2):1169–76.

    CAS  PubMed  Article  Google Scholar 

  108. 108.

    Yang N, Lode K, Berzaghi R, Islam A, Martinez-Zubiaurre I, Hellevik T. Irradiated tumor fibroblasts avoid immune recognition and retain immunosuppressive functions over natural killer cells. Front Immunol. 2020;11:602530.

    CAS  PubMed  Article  Google Scholar 

  109. 109.

    Li T, Yang Y, Hua X, Wang G, Liu W, Jia C, Tai Y, Zhang Q, Chen G. Hepatocellular carcinoma-associated fibroblasts trigger NK cell dysfunction via PGE2 and IDO. Cancer Lett. 2012;318(2):154–61.

    CAS  PubMed  Article  Google Scholar 

  110. 110.

    Farhood B, Najafi M, Mortezaee K. CD8(+) cytotoxic T lymphocytes in cancer immunotherapy: a review. J Cell Physiol. 2019;234(6):8509–21.

    CAS  PubMed  Article  Google Scholar 

  111. 111.

    Li Z, Zhou J, Zhang J, Li S, Wang H, Du J. Cancer-associated fibroblasts promote PD-L1 expression in mice cancer cells via secreting CXCL5. Int J Cancer. 2019;145(7):1946–57.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  112. 112.

    Costa A, Kieffer Y, Scholer-Dahirel A, Pelon F, Bourachot B, Cardon M, Sirven P, Magagna I, Fuhrmann L, Bernard C, et al. Fibroblast heterogeneity and immunosuppressive environment in human breast cancer. Cancer Cell. 2018;33(3):463-479 e410.

    CAS  PubMed  Article  Google Scholar 

  113. 113.

    Gao Y, Li X, Zeng C, Liu C, Hao Q, Li W, Zhang K, Zhang W, Wang S, Zhao H, et al. CD63(+) cancer-associated fibroblasts confer tamoxifen resistance to breast cancer cells through exosomal miR-22. Adv Sci (Weinh). 2020;7(21):2002518.

    CAS  Article  Google Scholar 

  114. 114.

    Luo H, Liu M, Luo S, Yu T, Wu C, Yang G, Tu G. Dynamic monitoring of GPER-mediated estrogenic effects in breast cancer associated fibroblasts: an alternative role of estrogen in mammary carcinoma development. Steroids. 2016;112:1–11.

    CAS  PubMed  Article  Google Scholar 

  115. 115.

    Pisano A, Santolla MF, De Francesco EM, De Marco P, Rigiracciolo DC, Perri MG, Vivacqua A, Abonante S, Cappello AR, Dolce V, et al. GPER, IGF-IR, and EGFR transduction signaling are involved in stimulatory effects of zinc in breast cancer cells and cancer-associated fibroblasts. Mol Carcinog. 2017;56(2):580–93.

    CAS  PubMed  Article  Google Scholar 

  116. 116.

    Santolla MF, Vivacqua A, Lappano R, Rigiracciolo DC, Cirillo F, Galli GR, Talia M, Brunetti G, Miglietta AM, Belfiore A, et al. GPER mediates a feedforward FGF2/FGFR1 paracrine activation coupling CAFs to cancer cells toward breast tumor progression. Cells. 2019;8(3):223.

    CAS  PubMed Central  Article  PubMed  Google Scholar 

  117. 117.

    De Marco P, Lappano R, De Francesco EM, Cirillo F, Pupo M, Avino S, Vivacqua A, Abonante S, Picard D, Maggiolini M. GPER signalling in both cancer-associated fibroblasts and breast cancer cells mediates a feedforward IL1beta/IL1R1 response. Sci Rep. 2016;6:24354.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  118. 118.

    Terry S, Savagner P, Ortiz-Cuaran S, Mahjoubi L, Saintigny P, Thiery JP, Chouaib S. New insights into the role of EMT in tumor immune escape. Mol Oncol. 2017;11(7):824–46.

    PubMed  PubMed Central  Article  Google Scholar 

  119. 119.

    De Francesco EM, Lappano R, Santolla MF, Marsico S, Caruso A, Maggiolini M. HIF-1alpha/GPER signaling mediates the expression of VEGF induced by hypoxia in breast cancer associated fibroblasts (CAFs). Breast Cancer Res. 2013;15(4):R64.

    PubMed  PubMed Central  Article  Google Scholar 

  120. 120.

    Kato T, Noma K, Ohara T, Kashima H, Katsura Y, Sato H, Komoto S, Katsube R, Ninomiya T, Tazawa H, et al. Cancer-associated fibroblasts affect intratumoral CD8(+) and FoxP3(+) T cells via IL6 in the tumor microenvironment. Clin Cancer Res. 2018;24(19):4820–33.

    CAS  PubMed  Article  Google Scholar 

  121. 121.

    Zhang Y, Cong X, Li Z, Xue Y. Estrogen facilitates gastric cancer cell proliferation and invasion through promoting the secretion of interleukin-6 by cancer-associated fibroblasts. Int Immunopharmacol. 2020;78:105937.

    CAS  PubMed  Article  Google Scholar 

  122. 122.

    King J, Mir H, Singh S. Association of cytokines and chemokines in pathogenesis of breast cancer. Prog Mol Biol Transl Sci. 2017;151:113–36.

    CAS  PubMed  Article  Google Scholar 

  123. 123.

    Zhao L, Huang S, Mei S, Yang Z, Xu L, Zhou N, Yang Q, Shen Q, Wang W, Le X, et al. Pharmacological activation of estrogen receptor beta augments innate immunity to suppress cancer metastasis. Proc Natl Acad Sci U S A. 2018;115(16):E3673–81.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  124. 124.

    Somasundaram A, Rothenberger NJ, Stabile LP. The impact of estrogen in the tumor microenvironment. Adv Exp Med Biol. 2020;1277:33–52.

    PubMed  Article  Google Scholar 

  125. 125.

    He M, Yu W, Chang C, Miyamoto H, Liu X, Jiang K, Yeh S. Estrogen receptor alpha promotes lung cancer cell invasion via increase of and cross-talk with infiltrated macrophages through the CCL2/CCR2/MMP9 and CXCL12/CXCR4 signaling pathways. Mol Oncol. 2020;14(8):1779–99.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  126. 126.

    Han R, Gu S, Zhang Y, Luo A, Jing X, Zhao L, Zhao X, Zhang L. Estrogen promotes progression of hormone-dependent breast cancer through CCL2-CCR2 axis by upregulation of Twist via PI3K/AKT/NF-kappaB signaling. Sci Rep. 2018;8(1):9575.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  127. 127.

    Benhadjeba S, Edjekouane L, Sauve K, Carmona E, Tremblay A. Feedback control of the CXCR7/CXCL11 chemokine axis by estrogen receptor alpha in ovarian cancer. Mol Oncol. 2018;12(10):1689–705.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  128. 128.

    Li RC, Wong MY, DiChiara AS, Hosseini AS, Shoulders MD. Collagen’s enigmatic, highly conserved N-glycan has an essential proteostatic function. Proc Natl Acad Sci U S A. 2021;118(10):e2026608118.

    PubMed  Article  CAS  Google Scholar 

  129. 129.

    Zhou S, Yin X, Mayr M, Noor M, Hylands PJ, Xu Q. Proteomic landscape of TGF-beta1-induced fibrogenesis in renal fibroblasts. Sci Rep. 2020;10(1):19054.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  130. 130.

    de Araujo R, Lobo M, Trindade K, Silva DF, Pereira N. Fibroblast growth factors: a controlling mechanism of skin aging. Skin Pharmacol Physiol. 2019;32(5):275–82.

    PubMed  Article  CAS  Google Scholar 

  131. 131.

    Surazynski A, Jarzabek K, Miltyk W, Wolczynski S, Palka J. Estrogen-dependent regulation of PPAR-gamma signaling on collagen biosynthesis in adenocarcinoma endometrial cells. Neoplasma. 2009;56(5):448–54.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  132. 132.

    Xu S, Xu H, Wang W, Li S, Li H, Li T, Zhang W, Yu X, Liu L. The role of collagen in cancer: from bench to bedside. J Transl Med. 2019;17(1):309.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  133. 133.

    Peng DH, Rodriguez BL, Diao L, Chen L, Wang J, Byers LA, Wei Y, Chapman HA, Yamauchi M, Behrens C, et al. Collagen promotes anti-PD-1/PD-L1 resistance in cancer through LAIR1-dependent CD8(+) T cell exhaustion. Nat Commun. 2020;11(1):4520.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  134. 134.

    Liu BW, Yu ZH, Chen AX, Chi JR, Ge J, Yu Y, Cao XC. Estrogen receptor-alpha-miR-1271-SNAI2 feedback loop regulates transforming growth factor-beta-induced breast cancer progression. J Exp Clin Cancer Res. 2019;38(1):109.

    PubMed  PubMed Central  Article  Google Scholar 

  135. 135.

    Lodyga M, Hinz B. TGF-beta1 - A truly transforming growth factor in fibrosis and immunity. Semin Cell Dev Biol. 2020;101:123–39.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  136. 136.

    Huo CW, Chew G, Hill P, Huang D, Ingman W, Hodson L, Brown KA, Magenau A, Allam AH, McGhee E, et al. High mammographic density is associated with an increase in stromal collagen and immune cells within the mammary epithelium. Breast Cancer Res. 2015;17:79.

    PubMed  PubMed Central  Article  Google Scholar 

  137. 137.

    Neugarten J, Acharya A, Lei J, Silbiger S. Selective estrogen receptor modulators suppress mesangial cell collagen synthesis. Am J Physiol Renal Physiol. 2000;279(2):F309-318.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  138. 138.

    Brodsky AS, Xiong J, Yang D, Schorl C, Fenton MA, Graves TA, Sikov WM, Resnick MB, Wang Y. Identification of stromal ColXalpha1 and tumor-infiltrating lymphocytes as putative predictive markers of neoadjuvant therapy in estrogen receptor-positive/HER2-positive breast cancer. BMC Cancer. 2016;16:274.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  139. 139.

    Zhao CL, Singh K, Brodsky AS, Lu S, Graves TA, Fenton MA, Yang D, Sturtevant A, Resnick MB, Wang Y. Stromal ColXalpha1 expression correlates with tumor-infiltrating lymphocytes and predicts adjuvant therapy outcome in ER-positive/HER2-positive breast cancer. BMC Cancer. 2019;19(1):1036.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  140. 140.

    Multhoff G, Vaupel P. Hypoxia compromises anti-cancer immune responses. Adv Exp Med Biol. 2020;1232:131–43.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  141. 141.

    Shea MP, O’Leary KA, Wegner KA, Vezina CM, Schuler LA. High collagen density augments mTOR-dependent cancer stem cells in ERalpha+ mammary carcinomas, and increases mTOR-independent lung metastases. Cancer Lett. 2018;433:1–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  142. 142.

    Terranova-Barberio M, Pawlowska N, Dhawan M, Moasser M, Chien AJ, Melisko ME, Rugo H, Rahimi R, Deal T, Daud A, et al. Exhausted T cell signature predicts immunotherapy response in ER-positive breast cancer. Nat Commun. 2020;11(1):3584.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  143. 143.

    Kristeleit R, Davidenko I, Shirinkin V, El-Khouly F, Bondarenko I, Goodheart MJ, Gorbunova V, Penning CA, Shi JG, Liu X, et al. A randomised, open-label, phase 2 study of the IDO1 inhibitor epacadostat (INCB024360) versus tamoxifen as therapy for biochemically recurrent (CA-125 relapse)-only epithelial ovarian cancer, primary peritoneal carcinoma, or fallopian tube cancer. Gynecol Oncol. 2017;146(3):484–90.

    CAS  PubMed  Article  Google Scholar 

  144. 144.

    Jiang XP, Yang DC, Elliott RL, Head JF. Reduction in serum IL-6 after vacination of breast cancer patients with tumour-associated antigens is related to estrogen receptor status. Cytokine. 2000;12(5):458–65.

    CAS  PubMed  Article  Google Scholar 

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This study was supported by grant from the National Natural Science Foundation of China (No. 81872181), the program of Zhejiang medical and health technology (2019KY079), Natural Science Foundation of Zhejiang Province (NO. LY20H160025, LY21H160034 and LY21H060003) and Zhejiang Xinmiao Talents Program (2020R401234).

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TCW, JKJ and CQ drafted most of the manuscript. JNL, JTL and AKX participated in the modification of the manuscript. KSX, LBJ and BL mainly drawing the schematic diagram. ZMY, HMT and WY participated in the review design. All authors read and approved the final manuscript.

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Correspondence to Zhengming Yang or Wei Yu.

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Wang, T., Jin, J., Qian, C. et al. Estrogen/ER in anti-tumor immunity regulation to tumor cell and tumor microenvironment. Cancer Cell Int 21, 295 (2021).

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  • Estrogen
  • Estrogen receptor
  • Tumor immunity
  • Tumor microenvironment
  • Cell differentiation