Estrogen is a widely studied female hormone and exists in three forms: estrone, estradiol, and estriol. Among them, estradiol is the most potent and prevalent in premenopausal women, playing a crucial role in the development of reproductive organs and maintenance of tissue homeostasis. Besides, estradiol and estrone can be interconverted by 17β-hydroxysteroid dehydrogenase, and estriol is primarily produced from the other two during pregnancy (24). Estrogen predominantly derives from ovary, corpus luteum, and placenta during reproductive periods; while is generated from kidneys, adipose tissue, skin, and brain in pre-puberty or post-menopause stage. In females, estrogen level fluctuates significantly across different physiological periods, with estradiol peaking during the menstrual cycle, estriol rising during pregnancy, and overall estrogen level declining during menopause, transitioning from ovarian to peripheral tissue production (25). Interestingly, males maintain relatively consistent level of estrogen throughout their adult life, while post-menopausal women have less estrogen than men of the same age (26).

Estrogen exerts its effects via the classic nuclear receptors, estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ), as well as novel membrane-associated receptors, G protein-coupled receptor 30, Gαq protein-coupled estrogen receptor, and ER-X. Notably, it has been reported that 88% of the human peripheral blood monocyte population is positive for ER (using a monoclonal antibody that recognizes both isoforms), providing direct evidence for ER expression in a key immune cell subset and supporting estrogen’s modulatory role in monocyte function. ERα is mainly expressed in uterus, liver, kidney, mammary gland, and adipose tissue, while ERβ can be found in lung, colon, cardiovascular system, and central nervous system (27, 28). For membrane-associated receptors, the former predominantly exists in adrenal medulla, renal pelvis, and ovary (28). Gαq-ER, though still in the early stage of research with its tissue distribution not yet fully established, is involved in rapid signal transduction via Gαq protein activation (29), while ER-X is known for its high-affinity binding in tissues like brain and uterus, particularly during postnatal development. Estrogen performs biological functions through different initiated pathways. Within the nuclear-initiated, estrogen interacts with ERα or ERβ, leading to translocation of the activated receptors from cell membrane to nucleus. The ERs then recruit transcriptional complexes and other co-regulatory factors to specific DNA sequences known as estrogen responsive elements, thereby modulating target gene transcription (30). This genomic action often involves the formation of ER homodimers or heterodimers on DNA. In addition, ERs also orchestrate a cascade of rapid estrogen responses through membrane-initiated signaling, far outpacing the above transcriptional process (31). These non-genomic signals are mediated by membrane-associated receptors and can rapidly activate pathways such as extracellular signal-regulated kinase)/mitogen-activated protein kinase, protein kinase C (elevating intracellular Ca²⁺), JNK/phosphatidylinositol 3 kinase, and cAMP-dependent transcription, which regulate critical cellular processes including apoptosis. At the receptor level, ERα and ERβ exhibit similar affinities for estradiol, whereas ERβ can antagonize and negatively regulate the function of ERα (32). ERα and ERβ are able to form homodimers or heterodimers within the cell nucleus; besides, ERα can also form heterodimers with androgen receptor (AR), thereby modulating the transcriptional activity (33).

Notably, estrogen modulates the functions of specific immune cell subsets (neutrophils, macrophages, CD4⁺ T cells) through these ER-mediated signaling pathways by regulating key transcription factors including peroxisome proliferator-activated receptor gamma (PPAR-γ); shaping cell-type dependent cytokine profiles such as promoting the secretion of interleukin (IL) -4, IL-6, and interferon gamma (IFN-γ) while inhibiting anti-inflammatory IL-10 and regulating IL-17A; and modulating the expression of surface receptors including C-X-C chemokine receptor type 2 (CXCR2), integrin alpha M, and toll-like receptor (TLR) 4. Detail mechanisms of ER-mediated sex-specific regulation in immune cells are elaborated subsequently.

Progesterone, also the principal female hormone, is integral to various physiological processes, including embryogenesis, puberty, menstrual cycle, and pregnancy. While primarily synthesized in the ovaries, a small amount of progesterone is also produced by the brain and adipose tissue. During reproductive years, progesterone fluctuates significantly, peaking in the luteal phase of menstrual cycle and rising substantially during pregnancy when the placenta takes over its production from the corpus luteum. After menopause, progesterone level drops sharply, with limited production continuing in peripheral tissues like adrenal glands. Beyond its reproductive role, progesterone is critical for maintaining tissue homeostasis and modulating the immune system, particularly preventing fetal rejection during pregnancy (34).

Functionally, progesterone exerts its effects by binding to specific receptors: progesterone receptor (PR) and, in some contexts, glucocorticoid receptor (GR). The PR is encoded by progesterone receptor gene, located on chromosome 11q22. PR-A and PR-B are two main isoforms of nuclear PR, which differ in structure and function. PR-B generally acts as a positive regulator of progesterone, while PR-A can modulate and, in some cases, antagonize the effects of PR-B (35). These receptors, upon binding to progesterone, translocate to the nucleus and interact with specific progesterone response elements on DNA, influencing the transcription of genes related to cell proliferation, differentiation, and maintenance of the reproductive tissues (34). In addition, progesterone also signals through membrane PRs (mPRs), such as mPRα and mPRβ, which mediate rapid, non-genomic actions. The receptors activate G-proteins, initiate intracellular signaling cascades, and affect key cellular processes like smooth muscle contraction, immune regulation, and apoptosis (36). For immune regulation, progesterone acts on macrophages and regulatory T cells (Tregs) via PR-mediated pathways, which involves inhibiting nuclear factor kappa-B (NF-κB) and upregulating forkhead box P3 (FOXP3) at the transcription factor level; reducing the release of pro-inflammatory cytokines including IL-6 and tumor necrosis factor-α while enhancing anti-inflammatory IL-10; and suppressing the formation of neutrophil extracellular traps (NETs) by neutrophils. Sex-biased immunomodulation of progesterone on cells is later discussed.

Androgens are a group of hydrophobic steroid hormones including testosterone, androstenedione, dihydrotestosterone and DHEA, and play an important role in maintaining male characteristics and physiological functions (37). Of these, testosterone is the most important in men, since it ensures the ability to produce sperm and participation in sexual activity. In addition, testosterone can also affect men’s physical strength, brain function, and heart health, which is equally important for women and helps maintain their overall health and sexual desire. In mammals, androgens are mainly synthesized and secreted by interstitial cells of the testis, with small amounts also produced by adrenal cortex and ovary. The level of androgen reaches peak during adolescence, and gradually decreases with age, especially over the age of 50, when its production declines by about one-third (37).

AR is a member of the ligand-activated transcription factor superfamily and mediates the effects of androgen. Among the hormones, only testosterone and dihydrotestosterone can bind to AR with high specificity and affinity, with the latter having approximately four times higher affinity than the former (38). Androgen exerts functions through both genomic and non-genomic pathways. Within the former, conformational change in the AR induced by ligand binding leads to the translocation of the receptor from cytoplasm to nucleus. The AR then acts as a homodimer and directly interacts with DNA at the androgen response element in the target gene regulatory region. In contrast, the non-genomic response occurs efficiently, and independently of gene transcription or protein synthesis, involving interactions with cell membrane-associated signaling molecules such as membrane receptors, ion channels or cytoplasmic regulatory proteins (38). Specifically, testosterone (the major androgen) mediates sex-biased immune cell functions in natural killer (NK) cells, CD8⁺ T cells, and neutrophils via AR-dependent genomic and non-genomic pathways, which involves suppressing interferon regulatory factor 8, activating forkhead box O1, and modulating T-Box transcription factor 21 at the transcription factor level; inhibiting the secretion of pro-inflammatory cytokines such as IL-1β and type I interferon (IFN)-γ; and regulating surface receptor expression by upregulating programmed death-ligand 1 (PD-L1) and downregulating natural killer group 2D. AR-dependent sex-specific functions in NK, CD8⁺ T cells, and neutrophils are systematically detailed thereafter.

It is noteworthy that, multiple sex hormone receptors (ERα/β, PR-A/B, and AR) all belong to the nuclear receptor superfamily and share common structural domains: the C-terminal ligand-binding domain, the variable N-terminal with a transcriptional activation function domain, the central DNA-binding domain, and the hinge region. The second transcriptional activation function domain is located within the C-terminal ligand-binding domain region and acts as an additional transcriptional activation area upon ligand binding (39). These structural similarities enable interactions between various sex hormones at multiple levels.

Sex chromosomes, comprising X and Y chromosomes, genetically determine the sex disparities from reproductive organs to the appearances/behaviors of adult individuals. The differentiation between X and Y chromosomes arises from their distinct evolutionary paths. X chromosome is larger and contains more amounts of genes, many of which are essential for basic cellular functions and immune responses (40). In contrast, the Y chromosome is smaller, expressing fewer genes, which are primarily related to male sex determination and spermatogenesis. Sex chromosomes can be classified into gonadal and non-gonadal actions. Due to the previous discussion on the effects of sex hormones, we mainly focus on the non-gonadal actions of sex chromosomes here.

Polymorphonuclear leukocytes (neutrophils) are the predominant type of leukocytes in peripheral blood and known to play a key role in the defense of pathogen invasion and external stimuli. As frontline immune responder, neutrophils are rapidly recruited to the sites of infection, and combat invading pathogens via multiple mechanisms, such as phagocytosis, degranulation, secretion of reactive oxygen species (ROS), and formation of NETs. However, excessive accumulation and dysfunction of these cells lead to abnormal inflammatory process and may ultimately determine patient outcomes (48). Meanwhile, neutrophils expresses both ER and AR, which largely affect its quantity, function, and fate (49). This aspect warrants further investigation for deeper insight in sex-specific differentiation of neutrophils (Figure 2) (Table 1).

Eosinophils orchestrate allergic response, anti-parasitic defense, and inflammatory modulation, whereas basophils initiate allergic cascades through histamine and inflammatory mediators release. Despite their immunological importance, research on sex differences in these granulocytes remains limited, with mechanistic insights particularly lacking (Table 2).

Pioneering observation in 1955 reveals sexually dimorphic eosinophil fluctuations in guinea pigs during physiological cycles, suggesting sexual hormonal modulation of the generation, maturation, and survival of eosinophils (79). Subsequent rodent studies identify estrogen’s regulatory capacity: it amplifies T helper 2 (Th2) cell polarization in allergic airways by enhancing IL-33 release from epithelial cells, thereby exacerbating eosinophilic inflammation via group 2 innate lymphoid cell activation (80, 81). Paradoxically, estrogen exhibits tumor-promoting effects in breast cancer models by suppressing tumoral and circulating eosinophils, which can be reversed with ERα blockade (82). This aforementioned differences in estrogen’s effects on eosinophils may stem from tumor microenvironment-specific signaling pathways or cell subset heterogeneity.

Basophil regulation displays contrasting hormonal dynamics. Clinical studies in idiopathic anaphylaxis patients demonstrate null effects of estrogen/progesterone on basophil histamine release (83). Conversely, androgens modulate basophil functionality indirectly via peripheral blood mononuclear cell-derived soluble factors, suppressing Th2 cytokine production and potentially explaining male-female disparities in allergic disease prevalence (84). In short, estrogen modulates eosinophil function via ERα-mediated IL-33/Th2 axis activation, while androgens indirectly regulate basophil functionality through suppressing Th2 cytokine production; progesterone shows no significant effect on basophil histamine release. This hormonal regulation explains the female predominance in allergic asthma (linked to eosinophilic inflammation) and the tumor-promoting effect of estrogen in breast cancer (via eosinophil suppression), as well as sex differences in the prevalence of allergic diseases.

T cells, the critical component of adaptive immune system, play an important role in immune surveillance and pathogen elimination through their diverse subtypes, including CD4⁺ T cells (T helper cells (Th) and Tregs and CD8⁺ cytotoxic T cells. Studies have shed light on potential sex-based disparities in T cells, which participate in the development and progression of various diseases (16, 85, 86). Mechanistically, T cell’s state and function can be largely regulated by estrogen or androgen signaling (87, 88), and even X/Y chromosome factors, affecting immune responses in physiological and pathological conditions (89, 90). Therefore, understanding the sex divergence of T cells is paramount for developing effective therapies for distinct diseases (Figure 3) (Table 3).

NK cells are innate lymphocytes that primarily exhibit cytotoxic effects by producing perforin, granzyme and IFN-γ in response to pathogens and malignant cells (123). However, research on their sexual dimorphism remains limited. Based on the observation that Coxsackievirus B3-associated myocarditis predominantly affects males, Zhou et al. explore that estrogen inhibits the expression of Th1-specific T-box transcription factor and the infiltration of cardiac IFN-γ⁺ NK cells, thereby preventing myocarditis in female (124). In Parkinson’s mice, NK cell from young female presents a higher expression of its receptors and IFN-γ production, which becomes less pronounced with aging (125). Androgens can also influence the function of NK cells. Elevated level of dihydrotestosterone reduces the cytotoxicity of NK cells, leading to their diminished ability to eliminate castration-resistant prostate cancer cells through the AR/PD-L1 signaling pathway (126). Furthermore, Liu et al. demonstrate that targeting AR, via either antiandrogen therapy or AR depletion, could enhance the tumor-killing efficacy of NK cells due to the decreased PD-L1 expression in bladder cancer (127) (Figure 4) (Table 2). Therefore, in NK cell, estrogen inhibits IFN-γ+ NK cell infiltration via suppressing Th1-specific transcription factors, while androgens reduce NK cell cytotoxicity through AR/PD-L1 signaling, leading to sex-specific NK cell functional differences. These differences explain the male predominance in Coxsackievirus B3-induced myocarditis and castration-resistant prostate cancer, as well as the potential of anti-androgen therapy to enhance NK cell-mediated tumor killing in bladder cancer.

Macrophages are versatile immune cells with diverse functions, mainly including eliminating pathogens, presenting antigens, and producing cytokines. They can polarize into pro-inflammatory (M1) or anti-inflammatory (M2) state, adapting to environmental signals to regulate immune response, tissue repair, and homeostasis (128). The regulation of sex-determining factors on macrophage function is diverse and complex. In infectious diseases, Q fever influences more males than females, despite a similar level of Coxiella burnetii exposure. It has been reported that the protective role of estrogen is achieved by enhancing the inflammatory profile of macrophages, whereas testosterone might affect disease progression via fostering an anti-inflammatory response (129). As one of the most important antibacterial mechanisms, phagocytic activity is markedly diminished in peritoneal macrophages from female mice subjected to ovariectomy compared with the sham group (57), while can be enhanced through treatment with estradiol or progesterone (130).

However, in inflammatory reactions, the situation is completely different. Estrogen-ERα axis exerts inhibitory action on the activation of TLR4 signaling and macrophage-associated inflammation, thereby promoting the stability of atherosclerotic plaques post-menopause (131). Another study claims that estradiol negatively modulates TLR4-induced M1 polarization and increases Th2 immune responses by activating serum-glucocorticoid regulated kinase 1 at the maternal-fetal interface, thus avoiding recurrent pregnancy loss (132). Besides, the anti-inflammatory role of allopregnanolone has also been identified in human macrophages via the inhibitory effects on both TLR4 and TLR7 activation, which lead to cytokine/chemokine reduction, particularly in female donors (133). When fed with high fat diet, ovariectomy increases the risk of non-alcoholic fatty liver disease in female mice. This is probably due to the inhibited recruitment and activation of M1 macrophages by estrogen-ERα signaling via the downregulation of CCR2 (134). In a mouse model of postmenopausal chronic stress, estradiol supplementation promotes the polarization of M1 to M2 macrophages in a β2-adrenoceptor-dependent manner, therefore facilitating the resolution of myocardial inflammation (135). Asthma is a chronic Th2 inflammation of the lung that affects more women than men in adulthood, with alveolar macrophage emerging as predominant mediator of the allergic inflammation. Estrogen-ERα axis is demonstrated to enhance IL-4-induced M2 polarization in asthmatic mice of both sexes challenged by ovalbumin (136, 137). Other findings also highlight the stronger IL-4 responsiveness in macrophages from female asthma patients than the males, leading to increased monocyte recruitment and M2 polarization in this disease (138). Sexually dimorphism is also prominent in pulmonary fibrosis, 5-hydroxytryptamine receptor 2C⁺alveolar macrophages specifically secrete angiopoietin-like protein 4, which mediates macrophage metabolic reprogramming, promoting lipolysis and inhibiting glycolysis, thereby suppressing grancalcin expression, reducing its accumulation in the lungs of female mice, and alleviating the pathological progression of pulmonary fibrosis (139). Notably, external stimuli like chemotherapy also trigger sex-specific macrophage responses: female macrophages upregulate intercellular adhesion molecule-1 more rapidly upon exposure, enhancing pro-inflammatory M1 polarization and release of pro-nociceptive factors and amplifying macrophage-peripheral nociceptor crosstalk, accelerating nociceptor activation and earlier onset of chemotherapy-induced neuropathic pain hallmarks (e.g., mechanical allodynia) in females (140). Further studies are needed to determine how macrophage polarization is specifically instructed by the pathological state (infection vs. autoimmunity) and local cytokine signals.

It is noteworthy that sex bias in macrophages not only attributes to sex hormones but may also be due to the chromosomes. Deny et al. discover that female macrophages exhibit higher level of chromosome X-linked microRNA-223-3p (miR-223-3p), which negatively correlates with pro-inflammatory M1 phenotype in Streptococcus agalactiae-associated pneumonia (141) (Figure 4) (Table 2).

Collectively, estrogen regulates macrophage polarization (M1/M2) via ERα/TLR4 and serum-glucocorticoid regulated kinase 1 pathways, testosterone fosters anti-inflammatory macrophage responses, and X-chromosome-linked miR-223-3p in females negatively correlates with M1 phenotype, jointly mediating sex bias in macrophage function. These regulatory effects underlie sex differences in Q fever susceptibility (male predominance), postmenopausal atherosclerotic plaque stability, asthma severity (female predominance), and non-alcoholic fatty liver disease risk.

Dendritic cells (DCs) are antigen-presenting cells and pivotal for initiating immune responses and maintaining immune tolerance (142). The action of sex-dependent DC functions in health and disease is complicated. Research has shown that ERα S-glutathionylation mediated by glutathione S-transferase Pi controls the differentiation and metabolic function of mouse dendritic cells (143). The estradiol-ERα signaling contributes to the strong sex bias on the capacity of plasmacytoid DC to produce IFN-1 in response to TLR7 (144, 145). Thus, targeting the ER signaling pathway in plasmacytoid DCs exhibits inhibitory effects on pathogenic generation of IFN-1 and autoantibodies, thereby preventing the progression of lupus-like syndrome in the initial stage of SLE (146, 147). The sexual dimorphism of DC function also appears in psoriasis, autoimmune encephalomyelitis and asthma. Selective ERα agonist enhances IL-23 secretion in DCs under LPS stimulation and aggravates pruritic responses in a psoriasis mouse model initiated by imiquimod (148). In encephalomyelitis, ERα signaling suppresses the neurotoxic function and maturation status of DC, which in turn impacts IL-12 and IFN-β production and ultimately modulates disease progression (149). With regard to asthma, estradiol elevates Th2-oriented CD103⁺ DCs in the bronchial lymph node, which may explain the higher prevalence and severity in female patients compared with the males (150). However, the activated IFN-1 signaling in bone marrow-derived DCs from 7-day-old female mice can also be protective in respiratory syncytial virus-related pneumonia, suggesting the diversity of sex dimorphism in DCs (151) (Figure 4) (Table 4). Jointly, estradiol-ERα signaling modulates plasmacytoid DC IFN-1 production and CD103⁺ DC Th2 polarization, while ERα S-glutathionylation controls DC differentiation and metabolic function, contributing to sex-specific DC-mediated immune responses. This sex dimorphism explains the female predominance in SLE (linked to pathogenic IFN-1 production by plasmacytoid DCs), psoriasis, and adult asthma, as well as the protective role of DC IFN-1 signaling in female respiratory syncytial virus-related pneumonia.

Group 2 innate lymphoid cells (ILC2s) are a unique subpopulation of immune cells with lymphocyte morphology but do not express lineage markers. ILC2s possess strong immune regulatory functions on allergic inflammation and tissue repair (152). Sexual dimorphism can be observed in ILC2s, though the conclusion is controversial. These conflicting ILC2 findings (elevated vs. no difference in asthma) may stem from asthma severity, sample source (circulating vs. sputum), or hormonal status (reproductive vs. post-menopause). Cephus et al. (153) claimed an elevated level of circulating ILC2s in women with moderate to severe asthma, while Aw et al. (154) observed higher sputum ILC2 numbers in female mild asthmatics. Yet, Wang et al. (155) reported no significant sex-based difference in the numbers of ILC2s in patients with asthma or allergic rhinitis (155). In asthmatic mouse model initiated by ovalbumin+IL-33, the females exhibit heightened type 2 inflammation, along with increased eosinophil influx and expansion of ILC2s, which may be attributed to greater IL-13 production compared to the males (156). Consistent with this finding, Wang et al. affirm higher levels of ILC2s and Th2 cytokines in female mice with the induction of IL-33 compared to the males. They further find a crucial protective role of testosterone in this allergic disease model (155). Mechanistically, AR signaling hinders the expansion and maturation of ILC2 and limits their responsiveness to IL-33 in type 2 airway inflammation (157). A more recent study published in Science try to unveil the mechanism underlying the sexual immune dimorphism: androgens negatively regulate ILC2 and the accumulation and activation of DCs in the skin, leading to the reduced tissue immunity in males (158) (Figure 4) (Table 4). In conjunction, androgen-AR signaling restrains ILC2 expansion, maturation, and responsiveness to IL-33, while female mice exhibit heightened ILC2-mediated type 2 inflammation, leading to sex differences in ILC2 function. These differences contribute to the higher prevalence and severity of asthma in females, as well as reduced tissue immunity in males (mediated by androgen-dependent ILC2 suppression).

B cells are central to humoral immunity, primarily functioning through antigen presentation, cytokine secretion, and antibody production. Significant sexual dimorphism exists in B cell biology, with females generally mounting stronger humoral responses than males. This is evidenced by higher baseline levels of immunoglobulins and more robust antibody production after vaccination or infection (159, 160). The enhanced B cell activity in females is a double-edged sword, contributing to both superior antiviral protection and a markedly higher susceptibility to systemic autoimmune diseases like SLE, where pathogenic autoantibodies are central (161).

The mechanisms are multifaceted, involving both hormonal and genetic pathways. At the hormonal level, estrogen promotes B cell activation and antibody diversification. It alters thresholds for B cell apoptosis and activation and has been shown to protect purified B cells from B cell receptor-mediated apoptosis (162). Concurrently, in vitro studies demonstrate that estrogen can significantly enhance antibody production, increasing the output of immunoglobulin G (IgG) and IgM from human B cells by more than two-fold (163). The hormone drives antibody diversification primarily through ER, which binds directly to the immunoglobulin heavy chain locus to participate in the three-dimensional DNA looping required for class-switch recombination, thereby influencing antibody isotype selection. This genomic action is specific to ERα, which is uniquely capable of disrupting B cell tolerance and permitting the survival of high-affinity autoreactive clones, directly linking this mechanism to female-biased autoimmunity (164–166). In contrast, testosterone tends to exert immunosuppressive effects, such as inhibiting germinal center formation (167, 168).

At the genetic level, contributions to the female bias in autoimmunity include incomplete X-chromosome inactivation, leading to biallelic expression of immune-related genes like Tlr7 in a subset of female immune cells. This results in a higher gene dosage and enhanced cellular responsiveness, such as lowered activation thresholds in B cells (169). Crucially, the maintenance of X-inactivation itself is actively regulated in B cells. Recent work shows that a B cell-specific X-inactive specific transcript complex enforces this silencing, and its dysfunction results in the expansion of pathogenic atypical B cells, directly linking the stability of X-inactivation to autoimmune B cell responses (170). These genetic mechanisms provide an explanation for the female bias in autoimmunity that is independent of, but potentially synergistic with, sex hormone effects. Additionally, B cells exhibit sex-based disparities in tumor immunity, and the regulation of B cell malignancy by sex hormones has been comprehensively reviewed elsewhere (159).

Previous study pointed that women consistently generate at least twice the amount of influenza vaccine-induced antibodies as men. Intriguingly, age acts as a key modifier of this sexual dimorphism. Immune and inflammatory responses are more robust in boys prior to puberty, with this advantage shifting to adult women post-puberty (171). Age-related hormonal shifts occur in both sexes: females experience reduced estrogen and progesterone, while males see declining testosterone. Such age-related hormonal decline during menopause and andropause directly reshapes immune cell functions by modulating sex hormone signaling (171–174). In detail, for menopause (female), postmenopausal estrogen drops by 60%-80%, reducing bone marrow GM-CSF secretion, impairing neutrophil maturation (25% lower mature proportion) and bacterial phagocytosis (52). Additionally, B and T cell counts decline (with fewer circulating lymphocytes vs. younger women), pro-inflammatory cytokines (IL-1β, IL-6, tumor necrosis factor-α) are markedly elevated, and T cell apoptosis increases following natural or surgical menopause. Estrogen-containing hormone replacement therapy in postmenopausal women improves immune function by increasing circulating B cell counts and reducing baseline pro-inflammatory cytokine levels, relative to non- hormone replacement therapy users. For andropause (male), studies indicate that low testosterone impairs CD4⁺T cell counts, Th1 responses, and Treg function; however, the impact of testosterone replacement therapy on immunity in aged men remains unreported (175–177).

Environmental factors serve as another critical modulator that can amplify or alter inherent immune sexual dimorphisms by interfering with sex hormone signaling pathways. The core mechanism involves environmental pollutants acting as endocrine disruptors, which can competitively bind to sex hormone receptors or affect their expression, thereby dysregulating normal hormone-immune communication (178). For instance, cigarette smoke may suppress the expression of ERα in lung tissue, attenuating the estrogen-mediated enhancement of neutrophil phagocytic function and consequently reducing the antibacterial capacity in female smokers. This is supported by clinical research showing that smoking causes a statistically significant decrease in phagocytic activity specifically in female subjects, impairing host defense functions (179, 180). Similarly, pollutants like PM2.5 are implicated in potentiating the inhibitory effects of androgens on immune cells such as NK cells, which may contribute to a gender-differential susceptibility to diseases like lung cancer (179). Animal studies reveal that the inflammatory response to particulate matter differs fundamentally by sex: exposed male mice show markers linked to acute inflammation (e.g., IL-1β, cyclooxygenase-2), whereas females exhibit increases in mediators like IL-17 that may promote chronic inflammation and tissue remodeling. Further evidence demonstrates that exposure to environmental stressors—including chlorine inhalation injury or prenatal stress, can lead to significant sex-based differences in immune cell migration, activation, and inflammatory responses (59, 178, 181).

Lifestyle factors are increasingly recognized as potential modulators of sexual dimorphism in immune responses, with growing evidence revealing sex-specific nuances in immune cell responses to these interventions beyond shared regulatory goals. For instance, dietary patterns such as high-fat diets can activate pathways that preferentially enhance estrogen-mediated M2 polarization of macrophages in females, contributing to differential metabolic disease susceptibility (182, 183). Similarly, the immunomodulatory effects of physical activity exhibit distinct sexual dimorphism (184). In males, aerobic exercise can elevate testosterone, which acts directly on CD4⁺T lymphocytes to increase the production of the anti-inflammatory cytokine IL-10 (185). Concurrently, exercise boosts Tregs’ frequency and suppressive capacity with post-pubertal males typically having more abundant, suppressive circulating Tregs than females (186, 187). Meanwhile, males show greater immune sensitivity to stress, due to androgens activating corticotropin-releasing hormone neurons expressing androgen receptors, enhancing hypothalamic-pituitary-adrenal axis activity and glucocorticoid release, which in turn triggers more intense apoptosis of immune cells like thymic T cells (188). These findings underscore that the impact of common lifestyle factors, though broadly beneficial, is precisely fine-tuned by biological sex at the level of specific immune cell subsets and functions.