Sex Differences in the Immune System and Their Implications | FreeS Research Institute

A modeling study published in The Lancet Public Health in 2024 offered fresh evidence for women's longevity advantage. This prospective study of the Chinese population projected that by 2035, average life expectancy in China could rise to 81.3 years — 85.1 years for women and 78.1 years for men.

But the differences between men and women extend beyond life expectancy to the immune system itself.

Sex differences in immunity have emerged as a research field only in the last five to ten years. Studies show that, overall, women have stronger immune capabilities than men. Research published in Immunity and Nature, for example, found that men infected with COVID-19 are more likely to develop severe illness and face higher mortality risk; men also face nearly double the risk of dying from malignant tumors.

But there's another side to this coin. Women are more susceptible to inflammatory and autoimmune diseases such as lupus, rheumatoid arthritis, and thyroid disorders.

Incorporating sex as a biological variable into oncology drug development and treatment represents an inevitable trend in medical progress — and a critical foundation for precision medicine.

In this research report, we'll explore sex differences in the immune system through the following questions:

• Why is the study of sex-based immune differences such a "new" field?
• Women vs. men: whose immune system is stronger?
• What causes these sex differences?
• What are the ultimate health impacts of these immune differences?
• Why should precision medicine account for sex differences?

We hope this offers a fresh perspective. If you're an entrepreneur or professional in biotech or pharma, feel free to reach out to the author, Lei Wang, Partner at FreeS Fund (lei@freesvc.com).

Reader Engagement

What innovation opportunities do you see in the immune space? Share your thoughts in the comments. By 17:00 on May 4, 2025, the three most thoughtful commenters will receive a copy of An Elegant Defense: The Extraordinary New Science of the Immune System.

/ 01 /

Why Is the Study of Sex Differences in Immunity Such a "New" Field?

Research on sex-based immune differences started late for specific historical reasons.

The most direct factor: from the late 1970s through the 1990s, biomedical research subjects in the U.S. were overwhelmingly male.

Initially, U.S. clinical trials included both men and women. But in the 1960s, thalidomide — a drug used to suppress morning sickness in pregnant women — was found to cause severe birth defects.

Though the drug had not yet received FDA approval and couldn't be formally marketed in the U.S., it had already entered the country through clinical trials. After the scandal broke, the drug was urgently recalled, but not before 17 American babies were born with phocomelia ("seal limb syndrome"), characterized by severely underdeveloped or absent limbs and low survival rates.

In response, the U.S. enacted the Kefauver-Harris Amendments, requiring FDA approval for all drug clinical trials. In 1977, the FDA issued General Considerations for the Clinical Evaluation of Drugs, explicitly banning women of childbearing potential from Phase I and Phase II clinical trials. Since this category covered ages 15 to 49, biomedical research subjects from 1977 through the 1990s were predominantly male.

While regulators intended to protect women and minimize risks to reproductive health, this created a new problem. With so few women in clinical trials for over a decade, many drugs — including some immunology and oncology agents — were approved by the FDA based on efficacy in male subjects, only to cause side effects or even death when administered to women.

Against this backdrop, in July 1993, the FDA issued guidelines for sex difference studies in drug clinical trials, reincorporating women into drug development. The guidelines provided direction for sex-specific clinical data analysis, evaluation of potential pharmacokinetic differences between sexes, and additional studies for women.

Yet even after women could participate in clinical trials, sex bias persisted in preclinical research.

For decades, researchers conducted animal experiments primarily on males — most notably in neuroscience. Beyond the mistaken belief that female hormones introduced unnecessary complexity, many researchers viewed the reproductive cycle of female animals as a potential confounding factor and opted for male subjects to achieve more stable results.

Since most common diseases show sex differences in prevalence, disease course, severity, and drug response, this severe sex bias from bench to bedside urgently needed correction. In 2014, the U.S. National Institutes of Health (NIH) proposed treating sex as a biological variable, requiring funded studies to use equal numbers of female and male animals and to analyze results by sex.

In summary, because women were long underrepresented in clinical research, studies of sex differences in the immune system naturally got a late start.

/ 02 /

Women vs. Men: Whose Immune System Is Stronger?

So — women vs. men, whose immune system is stronger?

Overall, women have stronger immune capabilities than men.

Consider these findings from research published in Immunity and Nature:

Men infected with COVID-19 are more likely to develop severe illness and face higher mortality risk;

During acute HIV infection, women have 40% less viral RNA in their blood than men;

Women receiving half the standard dose of inactivated influenza vaccine produce antibody concentrations equivalent to men receiving the full dose;

Men face nearly double the risk of dying from malignant tumors.

But there's another side to this coin.

Most autoimmune diseases occur in women. Autoimmune diseases — conditions where the immune system attacks the body's own tissues — include rheumatoid arthritis, multiple sclerosis, scleroderma, lupus, and Sjögren's syndrome.

In short, women mount stronger innate and adaptive immune responses than men. This enables women to clear pathogens faster and generate more robust vaccine efficacy, but also makes them more susceptible to inflammatory and autoimmune diseases.

/ 03 /

What Causes These Sex Differences?

At the mechanistic level, research by scholars AM Stoehr and H. Kokko at the University of California, Riverside, published in Behavioral Ecology, suggests one possibility: immune system operation demands substantial energy and resources, and males may have evolutionarily prioritized dampening immunity to gain stronger reproductive capacity.

Let's examine the mechanisms of sex-based immune differences in detail. Note that here we focus on biological sex, typically categorized as female, male, or intersex.

This categorization rests on three main factors:

• Sex chromosomes (e.g., 46,XX or 46,XY)
• Gonads (e.g., ovaries or testes)
• Gonadal hormones (e.g., estrogen or androgen)

Differences in sex chromosomes, gonads, and gonadal hormones produce substantial variation in immune system function.

I. Sex Chromosome Differences — A Key Source of Women's Immune Advantage

First, how do sex chromosomes influence immunity?

Humans have two sex chromosomes, X and Y. Women have XX chromosomes, with one X inherited from each parent. Men have XY, with X from the mother and Y from the father. The X chromosome contains over 1,000 genes, while the shorter Y chromosome carries only 45–75 genes.

With two X chromosomes, women avoid excessive gene expression by silencing one X chromosome during embryonic development. A few genes escape this process. For women, this means more opportunities for immune-related genes to be expressed — potentially giving women a naturally stronger immune system.

II. Sex Hormone Differences: Effective Modulators of Immune Response

Sex hormones play important regulatory roles in the immune system. Immune cells carry sex hormone receptors and can respond directly to these hormones.

Women's sex hormones consist mainly of estrogen and progesterone. Men's primary sex hormone is androgen.

Estrogen enhances immune response. It promotes antibody production and immune cell activity — such as enhancing proliferation and differentiation of B cells (white blood cells critical to adaptive immunity) and T cells (which actively defend against and eliminate infected cells) — while also regulating cytokine balance, promoting anti-inflammatory factor release and suppressing pro-inflammatory factors.

This anti-inflammatory effect has positive implications for reducing chronic inflammation and immune-related diseases.

Women's decreased resistance during menstruation stems from lower estrogen levels during this phase.

Progesterone is primarily secreted by the corpus luteum of the ovary, with the placenta also producing it during pregnancy. Progesterone suppresses maternal immune activity, reducing attacks on the fetus. Estrogen and progesterone maintain a certain balance, together regulating normal female reproductive function.

Similar to progesterone, androgens also have immunosuppressive effects. They inhibit T cell and B cell activity, reducing immune response intensity. This produces two outcomes: overall weaker immunity in men compared to women, but also lower incidence of autoimmune diseases.

Of course, immune system strength changes with age.

From embryo to adolescence to old age, hormone levels continuously shift.

In youth, sex hormones play major roles. Overall, women have stronger immune capabilities, but this also means young women face higher probability of acute autoimmune disease than men.

After menopause, especially in advanced age, women's estrogen secretion drops sharply, while the decline in androgen levels among older men is relatively more modest. One of the most notable features of immune system aging is abnormal chronic low-grade pro-inflammatory status, so older women experience higher rates of chronic low-grade inflammation than men of the same age.

/ 04 /

What Are the Ultimate Health Impacts of These Immune Differences?

Having introduced sex differences in immunity, we'll now analyze their deeper health impacts.

In the figure below, pink indicates diseases more common in women; blue indicates those more common in men.

Generally, women show higher susceptibility to autoimmune diseases, while men show higher susceptibility to non-reproductive system malignancies.

Graves' disease (diffuse toxic goiter, a hyperthyroid condition) and Hashimoto's thyroiditis (a hypothyroid condition) are both thyroid diseases more common in women.

Other autoimmune diseases more frequently seen in women include rheumatoid arthritis, lupus, and Type 1 diabetes.

According to 2022 estimates from the American Autoimmune Related Diseases Association (AARDA), approximately 50 million Americans (20% or one-fifth of the population) have autoimmune diseases, with about 75% (roughly 30 million) being women. The male-to-female ratio is 1:9 for lupus patients and 1:19 for Sjögren's syndrome patients.

Sex differences also exist in infectious diseases.

For instance, after HIV infection, women may have lower viral loads than men. Although women have stronger immune defenses, since HIV itself is an immune deficiency disease, women with equivalent viral loads may be more likely to develop AIDS. Men, meanwhile, appear more susceptible to hepatitis B and Ebola virus.

The figure above comes from a 2021 Nature study by University of Melbourne scholars Sue Haupt, Franco Caramia, and colleagues. You can see that for typical cancers such as lung cancer, colorectal cancer, and melanoma, incidence and mortality rates are substantially higher in men (light blue) than women (dark blue). Men should therefore be especially vigilant about these cancers.

Of course, we cannot attribute tumors entirely to the immune system. Tumor-related factors also include smoking, obesity, and inflammation.

Another important difference: women's average lifespan exceeds men's. Sex differences in the immune system may be a key factor influencing this lifespan gap.

We should also recognize that lifespan differences result from multiple combined factors. Beyond sex-based immune differences, smoking and obesity are more prevalent among men, and more men work in environments exposing them to ultraviolet radiation, dust, and toxic gases.

05

Sex Differences in Tumor Immunotherapy

Tumor immunotherapy represents one of the most promising treatment strategies in oncology.

According to studies published in PNAS, Nature, and Behavioral Ecology, because women generally have stronger immune systems, the tumor microenvironment in women may be more immunologically active. Women's relatively stronger immunity means immunotherapy may provide greater therapeutic benefit.

For example, immune checkpoint therapy blocks tumor immune escape, allowing the immune system to re-recognize and attack tumors. This approach currently shows better efficacy in female patients.

The figure above shows classic combination cancer treatment regimens — surgery, radiation, chemotherapy, targeted therapy, EGFR inhibitors, and immunotherapy — which are generally more effective in women, combining women's inherently stronger immune systems with tumor immunotherapy. But as noted earlier, the risk is that amplifying women's immune systems excessively could trigger backlash, increasing disease risk.

Although men have weaker immunity compared to women, this very fact means the benefits of tumor immunotherapy may be more readily apparent in men.

For the past decade, the industry has discussed precision medicine — designing personalized targeted treatments based on individual patients' tumor mutation profiles. Yet research on sex-differentiated treatment regimens remains in its early stages.

A journey of a thousand miles begins with a single step. Research on sex differences in the immune system will help advance precision medicine. We believe that in the future, more molecular truths will gradually be uncovered, potentially leading to discovery of new molecules and targets — such as hormones — that help reduce inflammation or lower allergy and autoimmune risk.

Research on sex differences in the immune system is an important and promising emerging field. After all, as ChatGPT 4o understands, "Sex differences do not divide us — they enrich us. By respecting and understanding our differences, we can better appreciate human diversity and beauty."

Reader Engagement What innovation opportunities do you see in the immune space? Share your thoughts in the comments. By 17:00 on May 4, 2025, the three most thoughtful commenters will receive a copy of An Elegant Defense: The Extraordinary New Science of the Immune System.

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