How Estrogen Signaling Helps Cancer Hide From the Immune System: What Patients Need to Know

Table of Contents

• Key Points
• Background: Why Immunotherapy Sometimes Fails
• The Estrogen Connection: How ERα Shapes the Tumor Environment
• Study Methods: How Researchers Investigated ERα and Melanoma
• Key Findings: Estrogen Fuels Immune Suppression
• Fulvestrant: Blocking Estrogen to Boost Immunotherapy
• Estrone vs. Estradiol: Two Estrogens, Different Effects
• Clinical Implications: What This Means for Breast Cancer Patients
• Study Limitations: What This Research Cannot Prove
• Recommendations: What Patients Should Know and Ask
• Frequently Asked Questions
• Source Information

Key Points

• Estrogen receptor signaling in macrophages suppresses CD8+ T cells, helping tumors evade immune attack.
• In mouse melanoma models, fulvestrant alone slowed tumor growth; combined with anti-PD-1 it worked even in resistant tumors.
• Antiestrogen therapy might help patients whose tumors lack estrogen receptors, because the effect is on immune cells.
• Fulvestrant plus immunotherapy has not yet been tested in humans; clinical trials are needed to confirm these findings.
• Obesity raises estrone levels, which may promote inflammation and cancer risk; maintaining a healthy weight is advisable.

Background: Why Immunotherapy Sometimes Fails

Immune checkpoint blockade (ICB) therapies are now a standard treatment for many solid tumors. These drugs work by "releasing the brakes" on the immune system, allowing the body's own T cells to recognize and attack cancer cells. Drugs such as pembrolizumab (Keytruda), nivolumab (Opdivo), and others have transformed care for cancers including melanoma, lung cancer, kidney cancer, and bladder cancer.

However, the reality is more complicated. While some patients experience exceptional, long-lasting responses, many others do not benefit at all. Two major problems limit the effectiveness of ICBs: intrinsic resistance (the tumor does not respond from the start) and acquired resistance (the tumor initially responds but later stops responding). Additionally, ICBs can trigger life-threatening side effects related to over-activation of the immune system, such as severe inflammation of the lungs, colon, or other organs.

This is why researchers are urgently seeking alternative strategies that can increase ICB responses without adding more toxicity. One promising avenue, explored in the study highlighted by this commentary, involves estrogen—a hormone most people associate with reproduction, but which also plays a powerful role in the immune system.

The Estrogen Connection: How ERα Shapes the Tumor Environment

One of the limitations of conventional cancer treatment is that it does not fully account for the interactions between tumor cells and their surrounding environment, known as the tumor microenvironment (TME). Most targeted cancer therapies focus on the cancer cells themselves, ignoring the essential "host" support cells—including immune cells, blood vessels, and fat cells—that surround the tumor. Healthy host cells are inherently more genetically stable than cancer cells, which means they could provide a less variable target for emerging therapies.

Estrogen receptor α (ERα) is a protein found in many different cell types throughout the body. Its activity is involved in multiple aspects of normal human physiology, including the growth and development of female reproductive tissues, bone integrity, cardiovascular and central nervous system functions, normal mammary (breast) development, and the immune response.

Studies have long suggested that sex differences in immune responses to cancer may be linked to circulating steroid hormones. A 2018 meta-analysis evaluating randomized trials of ICB agents across multiple cancer types—including melanoma, non-small cell lung cancer, renal cell (kidney) cancer, urothelial (bladder) cancer, head and neck cancer, gastric cancer, and mesothelioma—found that overall survival rates for men were substantially higher than those for women. However, that analysis excluded clinical trials of anti–PD-L1 drugs, and a more recent meta-analysis found that a patient's sex was not associated with ICB efficacy. The debate about true sex differences in immunotherapy response remains unresolved.

Nevertheless, evidence from patients who did not receive ICB therapy suggests that high estrogen levels and ERα signaling increase the risk of developing melanoma in women. Conversely, women with breast cancer who received adjuvant antiestrogen therapy had a lower risk of developing a second, primary melanoma compared with the general population. The study featured in this commentary (by Chakraborty and colleagues) is especially relevant because men also have circulating estrogens, meaning the findings could apply to cancers in both sexes.

Study Methods: How Researchers Investigated ERα and Melanoma

The researchers began by analyzing transcriptomic data sets—genetic information showing which genes are active—from patients with melanoma. Their goal was to test whether there were correlations between specific immune cell "signatures" in the tumor and how well patients responded to ICB therapy.

They focused on two types of suppressive myeloid cells commonly found in the tumor microenvironment: myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). Macrophages are immune cells that normally help clear infections, but in tumors, they can be "reprogrammed" to support cancer growth.

The key findings from this analysis were:

• MDSC signatures were not predictive of a patient's response to ICB therapy.
• A signature for polarized TAMs (macrophages that have shifted toward a specific activation state) was associated with response.
• Specifically, enrichment of the M1 macrophage gene signature—but not the M2 signature—was associated with better responses to ICB therapy.
• The M1/M2 ratio gene signature was associated with better overall survival in patients with melanoma receiving ICB therapy.

M1 macrophages are generally considered "pro-inflammatory" and help fight tumors, while M2 macrophages are "anti-inflammatory" and promote tumor growth. A higher M1/M2 ratio indicates a tumor environment more favorable to immune attack.

Building on these observations, the researchers hypothesized that ERα signaling was modulating the tumor microenvironment, leading to ICB resistance. They tested this theory using melanoma as a model because melanoma cells themselves express negligible levels of ERα—an important detail. This allowed the researchers to isolate the effects of estrogen signaling on the surrounding immune cells rather than on the cancer cells directly, establishing what scientists call a cancer cell–extrinsic mechanism.

Key Findings: Estrogen Fuels Immune Suppression

The preclinical studies produced several critical results. First, the researchers used three separate syngeneic murine melanoma models—mouse models in which the immune system is fully intact, allowing study of immune responses. In these models, they treated tumor-bearing mice that had undergone ovariectomy (removal of the ovaries, eliminating natural estrogen) with 17β-estradiol (E2), the most potent form of estrogen. E2 treatment led to increased tumor growth in all models.

They also used an autochthonous (spontaneously developing) mouse model of melanoma driven by the activated B-Raf^V600E mutation and homozygous deletion of the Pten gene. Again, E2 treatment led to increased tumor growth.

To understand how estrogen was promoting tumor growth, the researchers performed RNA-Seq (a technique that measures gene expression) on tumor-infiltrating immune cells. They found that E2 treatment caused significant changes in gene expression patterns in tumor-associated macrophages. When they eliminated ERα specifically from myeloid cells in mice, the immunosuppressive effects were reversed.

This led the researchers to a clear conclusion: ERα signaling increases the immunosuppressive activities of tumor-infiltrating myeloid cells. In plain terms, when estrogen binds to its receptor on macrophages within the tumor, it "teaches" those macrophages to suppress the activity of both CD4+ and CD8+ T cells—the very cells the immune system needs to kill cancer. This is a direct effect of estrogen on macrophages that suppresses the proliferation and activity of T cells.

Fulvestrant: Blocking Estrogen to Boost Immunotherapy

Having established that ERα signaling suppresses the immune response, the researchers asked a logical next question: Could blocking ERα with a drug improve the effectiveness of immunotherapy?

They turned to fulvestrant (brand name Faslodex), a selective estrogen receptor downregulator (SERD) that is already approved for the treatment of breast cancer. Unlike drugs that simply block estrogen from binding (like tamoxifen), SERDs cause the estrogen receptor to be degraded, essentially removing it from the cell.

The results were striking. In all three syngeneic melanoma models, substantial tumor growth inhibition was observed when fulvestrant was given alone, at a dose comparable to that used in patients with breast cancer. This means fulvestrant alone—without any immunotherapy—was able to slow melanoma growth by blocking ERα signaling and relieving immune suppression.

Even more promising was the combination approach. The researchers tested fulvestrant combined with anti–PD-1 immunotherapy (a checkpoint inhibitor targeting the programmed cell death 1 protein) in both PD-1–sensitive and PD-1–resistant melanoma models. In both models, the combination outperformed either single agent alone.

This is a critical finding. The fact that fulvestrant could restore sensitivity in a PD-1–resistant model suggests that adding antiestrogen therapy might help the roughly 60-70% of patients who do not respond to ICB therapy in the first place, as well as those whose tumors become resistant over time.

Taken together, the in vivo (living animal) studies indicate that pharmacological targeting of ERα can improve the efficacy of immune checkpoint inhibitors—a result with direct implications for human clinical trials.

Estrone vs. Estradiol: Two Estrogens, Different Effects

The commentary authors also raise an important scientific nuance: not all estrogens are the same. A critical issue in evaluating this research involves the choice of which estrogen is being studied. Recent data have shown that estrone (E1)—the estrogen that dominates after menopause—is not simply a slightly weaker version of estradiol (E2). Instead, E1 evokes a critically different ERα-regulated transcriptome (pattern of gene activation), with an emphasis on proinflammatory pathways mediated by a signaling molecule called NF-κB.

Here is the relevant biology in simpler terms:

• Before menopause, the ovaries produce large amounts of estradiol (E2), the most biologically potent estrogen.
• After menopause, ovarian E2 production declines dramatically, and estrone (E1) becomes the dominant estrogen. E1 is synthesized from adrenal androstenedione by the enzyme aromatase, primarily in fat tissue.
• In obesity, androstenedione synthesis remains unchanged, but its conversion (aromatization) to E1 in fat tissue increases.
• Consequently, women with obesity have two to four times higher E1 levels than women of normal weight.
• Both obesity and high E1 levels correlate with a greater risk of estrogen-receptor–positive breast cancer after menopause.

Adipocytes (fat cells) play an active role in this process. They mediate inflammation and immunosuppression by activating NF-κB and inducing cytokines (cell-signaling proteins). Adipose tissue releases cytokines that recruit macrophages and T cells, inducing chronic inflammation. An expanded pre-adipocyte population produces proinflammatory cytokines, including IL-6, IL-8, and CCL2, which drive pre-adipocyte proliferation and stimulate IL-1β and TNF-α, perpetuating a cycle of inflammation that supports tumor growth.

Recent experiments in breast cancer models indicate that the tumor-promoting activities of E2 are far less than those of E1. This may explain the mechanism by which receptor inactivation by SERDs (like fulvestrant) decreases the proinflammatory and immunosuppressive environment within tumors.

Understanding this distinction opens the possibility of blocking estrogen production entirely rather than just blocking its receptor. This could be accomplished using an aromatase inhibitor (AI)—drugs like letrozole, anastrozole, or exemestane that block the enzyme responsible for converting androgens into estrogens—in postmenopausal women. In premenopausal women, ovarian suppression therapy (using medications or surgery to stop ovarian estrogen production) could be combined with an aromatase inhibitor for a more complete blockade of both E1 and E2.

Clinical Implications: What This Means for Breast Cancer Patients

ICB therapy has proven effective for many solid tumors, but its efficacy in treating breast cancer has been modest. This is particularly relevant given the new understanding that ERα has cancer cell–extrinsic effects—meaning estrogen can promote tumor growth not by directly stimulating cancer cells, but by suppressing the immune system's ability to fight those cells.

Consider these important facts about breast cancer treatment:

• Antiestrogen therapies (like tamoxifen and aromatase inhibitors) are effective for ER-positive breast cancers, but they do not work in patients with ER-negative breast cancers, including triple-negative breast cancer (TNBC).
• Nearly one-third of patients with ER-positive disease receive no benefit from antiestrogen therapy.
• All patients with ER-positive metastatic breast cancer (MBC) ultimately become refractory (resistant) to all known antiestrogens.

Because of these limitations, several clinical studies have explored single-agent ICB therapy in patients with metastatic breast cancer. The results have been sobering but informative:

• In the KEYNOTE-086 study, the response rate to single-agent pembrolizumab in previously treated metastatic triple-negative breast cancer (mTNBC) was only 5.3%. However, a subset of patients with PD-L1–positive tumors who had not received previous treatment had an objective response rate (ORR) of 21.4%.
• In the KEYNOTE-028 study, single-agent pembrolizumab in PD-L1–positive advanced ER-positive breast cancer produced an ORR of 12.0%.

Although these overall response rates are modest, select patients do achieve durable responses—meaning their tumors shrink and stay controlled for extended periods. The challenge is identifying those patients and finding ways to turn non-responders into responders.

The commentary authors note that ER-positive breast cancer is thought to be relatively immunologically "cold" compared with TNBC. This means ER-positive tumors tend to have:

• Lower levels of CD8+ tumor-infiltrating lymphocytes (killer T cells that have entered the tumor)
• Less PD-L1 positivity on both tumor cells and immune cells
• A lower somatic mutational burden (fewer genetic mutations, which means fewer abnormal proteins for the immune system to recognize as foreign)

To date, clinical trials testing ICB for breast cancer have been conducted mainly in patients with mTNBC or ER-positive MBC who have already become refractory to antiestrogen therapy. This means the combination of ICBs with antiestrogens has yet to be tested—and given the new findings, it could prove highly effective in exactly these patient populations.

Perhaps most intriguing is the possibility that drugs like fulvestrant could have a role in tumors where the cancer cells themselves are ER-negative, such as TNBC or melanoma. Because estrogen's immunosuppressive effects are mediated through immune cells in the tumor microenvironment—not through the cancer cells—blocking ERα in immune cells could benefit patients regardless of whether their tumors express estrogen receptors.

Study Limitations: What This Research Cannot Prove

It is important to understand that the study highlighted in this commentary is a preclinical investigation—the experiments were conducted in mice and with patient data analyzed retrospectively. While the results are compelling, they cannot directly prove that antiestrogens will improve immunotherapy outcomes in humans.

The specific limitations include:

• Animal models do not perfectly replicate human disease. Murine melanoma models, while valuable, do not capture the full complexity of human tumors, the human immune system, or the effects of years of estrogen exposure.
• The transcriptomic analysis was correlational. The association between M1/M2 macrophage ratios and ICB response does not prove a cause-and-effect relationship.
• Sex differences in ICB response remain controversial. While earlier data suggested men respond better, more recent meta-analyses have not confirmed this, so the role of estrogen in human ICB responses is not fully settled.
• Fulvestrant has not yet been tested in combination with ICB in human cancer patients. The promising results in mice need confirmation in clinical trials.
• The commentary distinguishes between E1 and E2, but most existing clinical data on estrogen and cancer have focused on E2. More research is needed on the specific role of E1 in immunosuppression.

Additionally, this is a commentary article, not an original research paper. It summarizes and interprets the findings of the study by Chakraborty and colleagues, placing them in a larger scientific context. The viewpoints expressed are the authors' expert interpretations, not direct experimental results.

Recommendations: What Patients Should Know and Ask

For patients currently undergoing or considering cancer treatment, this research offers both hope and practical context. While no immediate changes to clinical practice are warranted based on this single study, the findings point toward important future directions:

1. For patients with breast cancer: If you have metastatic disease and have exhausted standard antiestrogen therapies, ask your oncologist whether clinical trials involving immunotherapy are available. The combination of antiestrogens with ICB has not yet been tested in trials, but this is an area of active interest.
2. For patients with melanoma: If you have not responded to immune checkpoint inhibitors or have developed resistance, discuss with your oncology team whether any clinical trials are exploring combination approaches, including hormonal agents.
3. For patients with triple-negative breast cancer: Even though your tumor cells may not express estrogen receptors, the new research suggests estrogen signaling in immune cells could still affect your tumor's ability to evade the immune system. This means antiestrogen therapy might someday be beneficial even for ER-negative disease.
4. Understand the context: A response rate of 5.3% or 12.0% in breast cancer trials sounds low, but it is important to remember that some patients experience durable responses—meaning long-term benefit. Researchers are working to identify which patients are most likely to benefit and how to expand that group.
5. Lifestyle considerations: The link between obesity, elevated estrone levels, and increased cancer risk (particularly ER-positive breast cancer after menopause) reinforces the importance of maintaining a healthy weight. This is not medical advice to begin a crash diet during treatment, but it is a factor worth discussing with your care team.
6. Watch for clinical trials: The commentary explicitly states that these results "provide a rationale for human trials to test the combination of antiestrogens with ICBs." Patients who are interested in emerging treatments should ask their oncologists about clinical trial registries and whether they might be eligible for any upcoming studies.

It is also worth noting that fulvestrant is already an approved, well-understood drug with a known safety profile. This could accelerate the path to clinical trials, as researchers already understand the drug's dosing, side effects, and interactions, potentially shortening the time needed to bring this combination approach to patients.

Finally, patients should understand that science moves step by step. The progression from mouse models to human trials is a necessary path, and while it can feel slow, each step builds the foundation for safer, more effective treatments. The findings highlighted in this commentary represent one such important step.

Frequently Asked Questions

What is immune checkpoint blockade and why does it sometimes fail?

Immune checkpoint blockade (ICB) uses drugs like pembrolizumab or nivolumab to release the brakes on T cells so they can attack cancer. However, many tumors do not respond at all (intrinsic resistance) or stop responding later (acquired resistance). ICB can also cause severe side effects from over-activation of the immune system, such as lung or colon inflammation.

How does estrogen affect the immune system's ability to fight cancer?

Estrogen binds to receptors on macrophages in the tumor and 'teaches' them to suppress CD4+ and CD8+ T cells, the immune cells needed to kill cancer. This happens through estrogen receptor α (ERα) signaling in these immune cells. Blocking this signaling can relieve that immune suppression and help T cells attack the tumor.

What is fulvestrant and how might it help with immunotherapy?

Fulvestrant is a drug already approved for breast cancer. It degrades estrogen receptors rather than just blocking them. In mouse melanoma models, fulvestrant alone slowed tumor growth. When combined with anti-PD-1 immunotherapy, it worked even in tumors that were resistant to anti-PD-1 alone, suggesting it could boost immunotherapy responses.

Could antiestrogen therapy help triple-negative breast cancer even though those tumors are ER-negative?

Yes, possibly. This research shows estrogen can promote tumor growth by acting on immune cells in the tumor environment, not directly on cancer cells. So even if a tumor lacks estrogen receptors, blocking estrogen signaling in immune cells might help the immune system fight the cancer. This has not yet been proven in humans.

What should melanoma patients who haven't responded to immunotherapy know from this research?

In mouse models, adding fulvestrant restored sensitivity to anti-PD-1 in resistant melanoma tumors. This suggests that combining antiestrogen drugs with immunotherapy might help some patients who do not respond initially or who become resistant. However, this combination has not been tested in human trials, so patients should ask their oncologist about clinical trial options.

What are the limitations of this research on estrogen and immunotherapy?

This was a preclinical study in mice, not humans. Mouse models do not fully capture human disease. The gene signature analysis was correlational, not proof of cause and effect. Also, sex differences in immunotherapy response remain controversial. Fulvestrant plus immunotherapy has not been tested in human patients, so clinical trials are needed to confirm these findings.

Are there clinical trials combining antiestrogens with immunotherapy?

The article states that clinical trials testing antiestrogens combined with immune checkpoint inhibitors have not yet been conducted. However, the findings provide a strong rationale for such trials. Since fulvestrant is already an approved drug with a known safety profile, researchers may be able to design trials more quickly. Patients interested in emerging treatments should ask their oncologist about trial registries.

Should I seek a second opinion about adding antiestrogen therapy to my immunotherapy for melanoma or breast cancer?

A second opinion can be valuable if you have melanoma or breast cancer and are considering whether antiestrogen therapy might improve your response to immunotherapy. Research in mouse models shows that blocking estrogen receptor signaling with fulvestrant can slow tumor growth and enhance anti-PD-1 immunotherapy, even in resistant tumors. However, this combination has not yet been tested in human trials, so no standard recommendation exists. A second opinion can help you understand whether you might be eligible for clinical trials exploring this approach and review your tumor's immune environment. Diagnostic Detectives Network provides independent expert second opinions.

Source Information

Original article title: role of estrogen receptor signaling in suppressing the immune response to cancer

Authors: James M. Rae and Marc E. Lippman

Journal: The Journal of Clinical Investigation (J Clin Invest), 2021;131(24):e155476. Published December 15, 2021. https://doi.org/10.1172/JCI155476

Type: Commentary article

Author affiliations: Dr. Rae is affiliated with the Division of Hematology and Oncology, Department of Internal Medicine, and the Department of Pharmacology at the University of Michigan Medical School, Ann Arbor, Michigan. Dr. Lippman is affiliated with the Georgetown Lombardi Comprehensive Cancer Center at Georgetown University, Washington, DC.

Related original research: The commentary discusses the study by Chakraborty et al., "Inhibition of estrogen signaling in myeloid cells increases tumor immunity in melanoma," published in the Journal of Clinical Investigation, 2021;131(23):e151347. https://doi.org/10.1172/JCI151347

Conflict of interest disclosure: Dr. Lippman has equity in and receives income from Seattle Genetics Inc.

This patient-friendly article is based on peer-reviewed research. It is intended for educational purposes and is not a substitute for professional medical advice. Patients should discuss all treatment decisions with their oncology care team.