bims-simsho 2025-10-26 papers

bims-simsho

Biomed News

on Systems immunology and sex hormones

Issue of 2025–10–26
25 papers selected by
Chun-Chi Chang, Lunds universitet

Sex differences in systemic sclerosis: from pathogenesis to clinical manifestations and treatment.
The interplay between vaginal microbiota and immune system in recurrent pregnancy loss and repeated implantation failure.
Plasma proteome adaptations during feminizing gender-affirming hormone therapy.
Hormone responses to buserelin in polycystic ovary syndrome and in eumenorrheic women with hyperandrogenism/hyperandrogenemia, and the relationship of these responses with insulin resistance.
Elevated testosterone is required for male sexual behaviour and dynamic colour change in veiled chameleons.
Overexpression of androgen receptor signalling transactivator lncRNAs PRNCR1 and PCGEM1 are associated with the increased risk of PCOS.
Insulin sensitivity and associated plasma proteomics during sex hormone therapy.
In vitro modeling of the female gut microbiome: effects of sex hormones and psychotropic drugs.
Negative association of psoriasis with female sex hormone levels: a case-control study using TriNetX.
Resident memory macrophages and trained innate immunity at barrier tissues.
Hippo signaling pathway in polycystic ovary syndrome.
Growth Hormone's Impact on Oxidative Stress, Ovarian Response, and In Vitro Fertilization in Polycystic Ovary Syndrome Across Different Ages.
Diving into High Concentration of EGCG: Assessing its Effects on miR-34 and miR-93, PSA, and AR Expression in Prostate Cancer LNCaP Cell Line.
Endometriosis-associated infertility: Multi-omics insights into pathogenesis and precision therapeutics.
Assessment of the Binding Patterns for Endocrine Disrupting Chemicals in Complex with Estrogen and Androgen Receptors by Leveraging the Asclepios Enalos KNIME Nodes.
IL-6 Inhibits Invasion in a Murine Model of Endometriosis.
The Role of the Microbiome in the Resolution of Infection-Induced Inflammation.
Natural killer cell activity in prostate cancer patients treated with curative radiotherapy with or without androgen deprivation therapy: an observational study.
Sexual Dimorphism in Systemic Inflammatory Responses to Femur Fracture in Mice Infected With SARS-CoV-2-Like Virus.
Unraveled role of TLR7-mediated interferon signaling activation in COVID-19.
Sexual dimorphism in neutrophil function: Unveiling the discriminative nature of male and female neutrophils.
Loss of androgen receptor expression is associated with aggressive tumor features and reduced survival in breast cancer patients.
Immunological Dynamics in PCOS T Cell Exhaustion TIGIT Upregulation Regulated by METTL3-Mediated N6 RNA Methylation.
Data-driven biomarker discovery and risk profiling for polycystic ovary syndrome in Indian women using ensemble learning.
Collagen-binding IL-12-armoured STEAP1 CAR-T cells reduce toxicity and treat prostate cancer in mouse models.

Ther Adv Musculoskelet Dis. 2025 ;17 1759720X251384602

Sex differences in systemic sclerosis: from pathogenesis to clinical manifestations and treatment.

Melpomeni Toitou, Maria Iacovantuono, Gesa Sauer, Carina Mihai, Maria Sole Chimenti, Oliver Distler, Cosimo Bruni, Muriel Elhai.

  Systemic sclerosis (SSc) exhibits sex-related disparities in prevalence, clinical features, and outcomes. While women are more frequently affected, men often experience a more severe disease course, including diffuse cutaneous involvement, interstitial lung disease, and reduced survival. These differences are shaped by biological factors such as sex hormones and genetic influences. Estrogens and androgens differentially influence immune and fibrotic pathways, while life stages such as menopause further modulate disease expression. Genetic mechanisms, including X chromosome inactivation, regulation of immune-related genes, and cell signaling pathways, vary between sexes and also play an important role in the sex bias seen in SSc. In addition to these biological aspects, gender, as a sociocultural factor involving roles, behaviors, and access to care, may further modify disease perception, healthcare engagement, and outcomes, though it remains underexplored in SSc research. Treatment responses may also vary by sex, as suggested by emerging studies, but sex-specific clinical recommendations are still lacking. This review aims to summarize current knowledge on sex-related differences in SSc and highlight implications for clinical management and future research.

Keywords:  epidemiology; gender; pathogenesis; prognosis; sex; sex differences; systemic sclerosis; treatment response

DOI:  https://doi.org/10.1177/1759720X251384602
J Reprod Immunol. 2025 Oct 20. pii: S0165-0378(25)00321-3. [Epub ahead of print]172 104743

The interplay between vaginal microbiota and immune system in recurrent pregnancy loss and repeated implantation failure.

Ala Amiri, Reza Kargar, Fakhri Sadat Hosseini, Maryam Hemmatzadeh, Hamed Mohammadi.

  Recurrent pregnancy loss (RPL) and repeated implantation failure (RIF) are significant reproductive challenges globally. Emerging evidence indicates that an imbalance in the vaginal microbiota significantly impacts the immune system, potentially leading to RIF and RPL. By searching databases PubMed/MEDLINE and Google Scholar by using relevant keywords and MeSH up to August 2025, this narrative review examines recent findings on vaginal microbiota-mediated immune alterations in women experiencing RIF and RPL. Our overview demonstrated that the vaginal microbiota, specifically Lactobacillus species, plays a key role in maintaining an anti-inflammatory environment conducive to successful pregnancy. Disruption of this balance, known as vaginal dysbiosis, can induce inflammation, immune dysregulation, and activation of pathogen-response pathways, potentially resulting in pregnancy loss. Moreover, the interaction between vaginal microbiota and both innate and adaptive immunities at the molecular level offers promising avenues for developing therapeutic strategies to manage dysbiosis-induced pregnancy complications.

Keywords:  Adaptive Immunity; Dysbacteriosis; Immunity, Innate; Recurrent Pregnancy Loss; Repeated Implantation Failure

DOI:  https://doi.org/10.1016/j.jri.2025.104743
Nat Med. 2025 Oct 20.

Plasma proteome adaptations during feminizing gender-affirming hormone therapy.

Nhi N L Nguyen, Den Celestra, Lachlan M Angus, Toby Mansell, Rebecca Shepherd, Bo Won Kim, Bridget Arman, Georgiana Cabau, Tania O Crișan, Leo A B Joosten, Camille Laberthonnière, David Burgner, Gilda Tachedjian, Musa Mhlanga, Rachel A Davey, Ken C Pang, Ada S Cheung, Richard Saffery, Boris Novakovic.

Sex differences manifest in various traits, as well as in the risk of cardiovascular, metabolic and immunological conditions. Despite the clear physical changes induced by gender-affirming hormone therapy (GAHT), little is known about how it affects underlying physiological and biochemical processes. Here we examined plasma proteome changes over 6 months of feminizing GAHT in 40 transgender individuals treated with estradiol plus one of two antiandrogens: cyproterone acetate or spironolactone. Testosterone levels dropped markedly in the cyproterone group, but less so in those receiving spironolactone. Among 5,279 total proteins measured, feminizing GAHT changed the levels of 245 and 91, in the cyproterone and spironolactone groups, respectively, with most (>95%) showing a decrease. Proteins associated with male spermatogenesis showed a marked decrease in the cyproterone group, attributable specifically to loss of testosterone. Changes in body fat percentage and breast volume following GAHT were also reflected in the plasma proteome, including an increase in leptin expression. We show that feminizing GAHT remodels the proteome toward a cis-female profile, altering 36 (cyproterone) and 22 (spironolactone) of the top 100 sex-associated proteins in UK Biobank adult data. Moreover, 43% of cyproterone-affected proteins overlapped with those altered by menopausal hormone therapy in cis women, showing the same directional changes, with notable exceptions including CXCL13 and NOS3. Feminizing GAHT skewed the protein profile toward that linked to asthma and autoimmunity, while GAHT with cyproterone specifically skewed it away from an atherosclerosis-associated profile, suggesting a protective effect. These results reveal that feminizing GAHT reshapes the plasma proteome in a hormone-dependent manner, with implications for reproductive capacity, immune regulation and long-term health outcomes.

DOI: https://doi.org/10.1038/s41591-025-04023-9
J Clin Transl Endocrinol. 2025 Dec;42 100420

Hormone responses to buserelin in polycystic ovary syndrome and in eumenorrheic women with hyperandrogenism/hyperandrogenemia, and the relationship of these responses with insulin resistance.

Salvatore Benvenga, Michele Russo, Fausto Famà, Gianpiero Forte, Vittorio Unfer.

  We compared 37 women with polycystic ovary syndrome (PCOS) with 24 women with eumenorrhea plus hyperandrogenism and/or hyperandrogenemia without ultrasound evidence of PCO morphology (EuHyperA) to assess their hormone responses to a GnRH-agonist (buserelin). Following our recent paper on PCOS and EuHyperA, we selected patients who performed the 2 h-oral glucose tolerance test (OGTT), and stratified them according to presence/absence of insulin resistance (IR), viz. HOMA-index ≥ 2.5. IR impacted on the PCOS group since IR-yes-PCOS women had significantly higher body weight, BMI, total testosterone (TT), free androgen index (FAI), and 17-hydroxyprogesterone (17-OHP), borderline higher delta-4 androstenedione (Δ4-ASD) and ovarian volume, and significantly lower sex hormone-binding globulin (SHBG) vs IR-no-PCOS. IR-no-EuHyperA had significantly higher follicle-stimulating hormone (FSH), borderline higher dehydroepiandrosterone sulfate (DHEAS) and borderline lower 17-OHP vs IR-no-PCOS. IR-yes-EuHyperA had significantly higher DHEAS, borderline lower TT and FAI vs IR-yes-PCOS. The insulin curve was significantly higher in the IR-yes vs IR-no-PCOS, and IR-yes vs IR-no-EuHyperA. Compared to PCOS, EuHyperA had insignificantly lower glucose and insulin responses regardless of IR status. After steroidogenic ovarian stimulation (24 h-buserelin test), IR presence vs IR absence impacted on 4 curves in PCOS (significantly higher TT, borderline higher 17-OHP, significantly lower Δ4-ASD and DHEAS), and only one curve in EuHyperA (significantly higher TT). IR-no-EuHyperA had two curves significantly lower than IR-no-PCOS (Δ4-ASD and TT). Instead, IR-yes-EuHyperA had significantly lower Δ4-ASD, TT and 17-OHP curves, and significantly higher DHEAS curve vs IR-yes-PCOS. In conclusion, of 35 parameters (baseline, OGTT-related, buserelin-related), 28 (80%) were statistically similar in EuHyperA vs PCOS regardless of IR status. However, IR presence impacted on more parameters in PCOS than EuHyperA. Given the known ovary sparing by IR in PCOS, it appears that IR exacerbates androgen production of PCOS women more markedly than EuHyperA women.

Keywords:  17-OH-progesterone; Eumenorrhea; Gonadotropin-releasing hormone-agonist test; Hyperandrogenemia; Hyperandrogenism; Insulin resistance; Polycystic ovary syndrome

DOI:  https://doi.org/10.1016/j.jcte.2025.100420
Sex Dev. 2025 Oct 20. 1-20

Elevated testosterone is required for male sexual behaviour and dynamic colour change in veiled chameleons.

Anna Bauerová, Lukáš Kratochvíl, Lukáš Kubička.

INTRODUCTION: Sex-specific genotype and early organization can influence the expression of sexually dimorphic traits in vertebrates. We tested these hypotheses in male-typical behaviour and rapid change to bright colouration in the veiled chameleon (Chamaeleo calyptratus) with XX/XY sex chromosomes.
METHODS: Hormonal manipulations included castration with and without testosterone replacement, and testosterone administration in females.
RESULTS: Long-term testosterone treatment induced male-typical sexual behaviour and an ability to switch to bright colouration in females, while castration suppressed these traits in males. These observations document that elevated testosterone alone is sufficient for the expression of these traits in both males and females. Surprisingly, high testosterone levels led to indiscriminate courtship behaviour, with frequent mating attempts directed at conspecifics regardless of their sex and testosterone level in both home cages and neutral arenas. This unexpected behaviour suggests that visual cues, such as body and head-casque size, may not reliably guide sex recognition during short distance encounters.
CONCLUSION: The dependence of the male-typical sexual behaviour and colour change on the elevated androgen levels contrast sharply with earlier results on skeletal traits (body size and head-casque size), which are fully developed in castrated males, demonstrating that the ontogeny of the sex-typical phenotype involves different mechanisms in the emerging model species of chameleons.

DOI: https://doi.org/10.1159/000548930
Sci Rep. 2025 Oct 22. 15(1): 36833

Overexpression of androgen receptor signalling transactivator lncRNAs PRNCR1 and PCGEM1 are associated with the increased risk of PCOS.

Mudasar Nabi, Shayaq Ul Abeer Rasool, Sairish Ashraf, Syed Mudasir Andrabi, Shajrul Amin.

  PCOS, a common disorder in reproductive aged women, characterized by hyperandrogenism. Hyperandrogenism can be attributed to the hyperactive androgen receptor (AR). Androgen receptor mediated signalling involves the association of multiple coregulators and any aberrant activity of these factors may disrupt the normal transcriptional activity of AR and hence may act as contributing factors in pathophysiology of hyperandrogenic disorders. LncRNAs PRNCR1 and PCGEM1 act as AR coactivators. The study was aimed at determining the association of these lncRNAs with PCOS. A total of 178 participants including 105 PCOS cases and 73 controls were recruited. The Anthropometric, Metabolic and hormonal characteristics of the participants were determined. Total RNA was isolated and reverse transcribed into cDNA. Quantitative real-time PCR was done to study the expression pattern of lncRNAs. The association between different parameters with the expression of PRNCR1 and PCGEM1 was determined by correlation analysis. The expression levels of PRNCR1 (PRNCR1, 5.28 (1.29-9.14) versus 1.07 (0.05-3.18); P < 0.001) (PCGEM1, 3.08 (0.29-8.79) versus 1.70 (0.116-3.73); P < 0.001) were significantly higher in Women with PCOS compared to controls. Furthermore, lncRNA PRNCR1 showed a positive correlation with testosterone (P < 0.001). ROC analysis showed a strong diagnostic performance of lncRNA PRNCR1 Optimal Cut off (Youden's Index) = 3.23, AUC = 0.988 (95% CI = 0.976-0.99) and Sensitivity = 0.91, Specificity = 1.00 and for PCGEM1 Optimal Cut off (Youden's Index) = 2.02, AUC = 0.86 (95% CI = 0.81-0.92) and Sensitivity = 0.82, Specificity: 0.90. Our results demonstrated that overexpression of AR coactivator lncRNAs PRNCR1 and PCGEM1 are associated with an increased risk of PCOS in Kashmiri women. These lncRNAs may act as important factors for the hyperactivation of AR and subsequent overexpression of AR regulated genes and thus may contribute towards the pathogenesis of PCOS and its clinical manifestations.

Keywords:  Hyperandrogenism; LncRNA; PCGEM1 and polycystic ovaries; PRNCR1

DOI:  https://doi.org/10.1038/s41598-025-16655-5
J Clin Endocrinol Metab. 2025 Oct 22. pii: dgaf573. [Epub ahead of print]

Insulin sensitivity and associated plasma proteomics during sex hormone therapy.

Sarah van Eeghen, Laura Pyle, Phoom Narongkiatikhun, Ye Ji Choi, Taryn Vosters, Irene van Valkengoed, Petter Bjornstad, Sarah Siegelaar, Natalie Nokoff, Martin den Heijer, Daniël van Raalte.

   PURPOSE: Women are generally protected against insulin resistance and related comorbidities when compared with men, potentially due to the role of sex hormones. While epidemiological and animal studies suggest that sex hormones may impact insulin sensitivity, studies in humans on the effects of estradiol and testosterone treatment on insulin sensitivity assessed by gold-standard measures remain limited. The molecular mechanisms involved are also not well understood. Therefore, we aimed to investigate changes in insulin sensitivity and associated change in plasma proteome following three months of sex hormone therapy.
METHODS: This prospective, observational study included 29 individuals initiating feminizing (estradiol with gonadotropin-releasing hormone analogue; n=16) or masculinizing (testosterone; n=13) therapy. Measurements at baseline and after three months included insulin sensitivity, assessed via hyperinsulinemic-euglycemic clamp (M-value; adjusted for lean body mass and M/I ratio; M-value adjusted for plasma insulin concentrations), along with plasma proteomics.
RESULTS: During feminizing hormone therapy, insulin sensitivity increased (M-value: +23.3%, M/I ratio: +20.2%; p<0.05), whereas during masculinizing hormone therapy, no changes were observed. Of the differentially expressed plasma proteins (49 during feminizing, and 356 during masculinizing hormone therapy), 16 correlated with changes in insulin sensitivity. Several were involved in immunoregulation and inflammation (vascular endothelial growth factor D, 5'-nucleotidase), iron homeostasis and erythropoiesis (hepcidin, transferrin receptor protein 1:cytoplasmic domain), and oxidative stress (superoxide dismutase 3).
CONCLUSIONS: Feminizing hormone therapy, characterized by high serum estradiol and low serum testosterone concentrations, enhanced insulin sensitivity. These findings highlight the impact of sex hormones on insulin sensitivity and may inform sex-specific precision medicine.

Keywords:  Estradiol; Insulin sensitivity; Plasma proteomics; Sex hormone therapy; Sex hormones; Testosterone

DOI:  https://doi.org/10.1210/clinem/dgaf573
Microbiol Spectr. 2025 Oct 20. e0235025

In vitro modeling of the female gut microbiome: effects of sex hormones and psychotropic drugs.

Luana Leao, Galal Ali Esmail, Saba Miri, Walid Mottawea, Riadh Hammami.

  Sex hormones play a crucial role in shaping gut microbiome composition and metabolism, with significant implications for mental health. This study investigated the effects of sex hormones and the psychotropic drug aripiprazole on the gut microbiome, using a novel in vitro colonic fermentation model adapted from the PolyFermS system. Fecal samples from four male and female donors were used to develop sexually divergent models, with the female model subjected to hormonal treatments mimicking different phases of the menstrual cycle. Microbiome composition and short-chain fatty acid (SCFA) metabolism were analyzed. The results demonstrated that sex hormones significantly influenced microbiota structure and diversity, with the female model exhibiting reduced α-diversity and distinct bacterial associations with SCFAs. Hormonal fluctuations across menstrual phases induced specific shifts in bacterial composition, notably increasing Bacteroidota while decreasing Bacillota and Pseudomonadota. In the female model, aripiprazole treatment led to increased microbial diversity and altered SCFA profiles, although the changes in SCFAs were not statistically significant (P > 0.05). Differential abundance analysis revealed sex-specific enrichment of bacterial genera, such as Eubacterium coprostanoligenes and Agathobacter. These findings underscore the importance of considering sex-specific microbiome profiles and hormonal influences when optimizing psychotropic treatments for mental health disorders.IMPORTANCEThe gut microbiome plays a crucial role in human health, affecting metabolism, immunity, and brain function. However, the role of sex hormones in shaping the gut microbiome composition and metabolism remains largely unexplored. This study introduces a novel in vitro colonic fermentation model to investigate the effects of sex hormone fluctuations and psychotropic drug exposure on the gut microbiome. By simulating a sexually divergent human colon environment and mimicking hormonal variations throughout the menstrual cycle, this model provides a controlled setting for studying microbiome response to external stimuli. Our findings revealed that sex hormones, such as estrogen, progesterone, and testosterone, shape microbial diversity and alter the microbiome composition compared to the control group. Additionally, this study examined the effect of psychotropic drug exposure on the microbiota of a simulated female colon, revealing alterations in the microbial composition and metabolism. These results highlight the importance of considering the role of the gut microbiome in drug response, given the widespread use of psychiatric medications, particularly among women. This novel colonic fermentation model offers a valuable tool for studying sex-specific microbiome dynamics and their broader implications for health.

Keywords:  colon model; gut microbiota; in vitro fermentation; psychotropic medication; sex hormones; sex-specific effects; short-chain fatty acids

DOI:  https://doi.org/10.1128/spectrum.02350-25
J Am Acad Dermatol. 2025 Oct 17. pii: S0190-9622(25)03029-4. [Epub ahead of print]

Negative association of psoriasis with female sex hormone levels: a case-control study using TriNetX.

Alexa S Podolsky, Amit Singal, Shari R Lipner.



Keywords:  dehydroepiandrosterone-sulfate; estradiol; estrogen; progesterone; psoriasis; sex hormones; testosterone

DOI:  https://doi.org/10.1016/j.jaad.2025.10.059
Elife. 2025 Oct 20. pii: e106549. [Epub ahead of print]14

Resident memory macrophages and trained innate immunity at barrier tissues.

Alisha Kang, Michael D'Agostino, Sam Afkhami, Mangalakumari Jeyanathan, Zhou Xing.

  Innate immune memory, or trained innate immunity (TII), represents a form of immunological adaptation in which innate immune cells, including myeloid and lymphoid cells, retain a trained state following prior exposure to immunological stimuli. This long-lasting modification either enhances or reduces the innate immune response to subsequent heterologous infections or inflammatory insults. While TII often provides protective benefits, including enhanced protection against pathogens and tumors, it can contribute to maladaptive inflammation in certain conditions. Epigenetic changes and metabolic reprogramming are key drivers of innate immune memory, but it is important to distinguish between transient acute changes and persistent modifications that define bona fide innate immune memory. Innate immune memory can be induced centrally, through systemic events that train hematopoietic progenitors in the bone marrow, or locally, via tissue-resident cells such as macrophages. The presence of trained tissue-resident immune cells offers significant advantages, but their responses may not always result in universally enhanced protection. This review explores recent advances in the understanding of tissue-resident memory macrophages and TII at barrier tissue sites, including the lung, skin, gut, and peritoneum, highlighting the implications for vaccine and immunotherapeutic strategies. Ongoing research promises to accelerate progress in this field and inform new clinical and vaccinology approaches.

Keywords:  barrier tissues; immunology; inflammation; lung; memory macrophages; trained immunity; vaccine

DOI:  https://doi.org/10.7554/eLife.106549
Front Endocrinol (Lausanne). 2025 ;16 1623143

Hippo signaling pathway in polycystic ovary syndrome.

Jiahui Wen, Guan Cheng, Yan Zhang, Su Liu.

  Polycystic ovary syndrome (PCOS) is a complex endocrine-metabolic disorder syndrome, that predominantly affects women of reproductive age. It is characterized by marked clinical heterogeneity involving multiple systems including reproductive, metabolic and immune systems, while existing diagnostic protocols remain inadequate for clinical needs. Moreover, the incomplete understanding of PCOS etiology has limited therapeutic strategies for symptomatic management rather than interventions targeting core pathological mechanisms, resulting in PCOS frequently persisting as a chronic condition with an increased risk of long-term complications such as type 2 diabetes, metabolic disorder-associated fatty liver disease and cardiovascular disease. This clinical reality underscores the urgent need to elucidate its pathogenic network at the molecular level. Emerging evidence suggests that the Hippo signaling pathway plays a central role in the pathological process of PCOS through dynamically regulating cell proliferation-apoptosis balance, differentiation programs and metabolic homeostasis. This review examines the molecular mechanisms governing Hippo signaling transduction and its physiological relevance, with a focused analysis of its diverse implications in PCOS pathophysiology, particularly in reproductive dysfunction, metabolic-endocrine disturbances, and immune dysregulation. These mechanistic insights not only advance our understanding of PCOS pathogenesis but also provide a theoretical foundation for developing signaling pathway-targeted precision therapies.

Keywords:  Hippo signaling pathway; TAZ; YAP; inflammation; insulin resistance; lipid metabolism; ovary; polycystic ovary syndrome

DOI:  https://doi.org/10.3389/fendo.2025.1623143
Br J Hosp Med (Lond). 2025 Oct 25. 86(10): 1-18

Growth Hormone's Impact on Oxidative Stress, Ovarian Response, and In Vitro Fertilization in Polycystic Ovary Syndrome Across Different Ages.

Panpan Zhao, Xiliang Wang, Qian Zhang, Yinling Xiu, Kaixuan Sun, Yuexin Yu.

  Aims/Background Growth hormone (GH) supplementation contributes to improved reproductive and pregnancy outcomes in in vitro fertilization (IVF)-embryo transfer (ET) in polycystic ovary syndrome (PCOS) women. This study aimed to explore the effects of GH on the oxidative stress, ovarian reactivity, and pregnancy outcomes of IVF-ET in PCOS patients of different ages. Methods The clinical data of 342 women with PCOS undergoing in vitro fertilization/intracytoplasmic sperm injection-embryo transfer (IVF/ICSI-ET) were collected for retrospective analysis. Based on age, patients were divided into three groups: <35 years (n = 118), 35-40 years (n = 120), and >40 years (n = 104). Each age group was further subdivided into a GH subgroup and a control subgroup, according to whether GH was supplemented during ovarian stimulation. Ovarian stimulation parameters and IVF/ICSI-ET outcomes were recorded. Levels of malondialdehyde (MDA) and superoxide dismutase (SOD) in both follicular fluid and serum were measured using commercial assay kits. Results In the 35-40 years group, the total number of oocytes retrieved, metaphase II (MII) oocytes, and ovarian sensitivity index (OSI) were significantly higher in the GH group compared to the control group (p = 0.012, 0.049, 0.006, respectively). In the >40 years group, the total number of oocytes retrieved and OSI were also significantly increased in the GH group compared to the control group (p = 0.001, 0.002, respectively). In the <35, 35-40, and >40 years groups, the serum SOD level on the trigger day was significantly higher in the GH groups than in the control groups (p = 0.004, 0.001, 0.012, respectively), while the serum MDA level was significantly lower (p = 0.032, 0.015, 0.004, respectively). In the 35-40 and >40 years groups, the fertilization rate was significantly higher in the GH subgroups compared to the control subgroups (p = 0.040, 0.001, respectively). A total of 43 ET cycles were cancelled, and 299 ET cycles were analyzed. In the 35-40 years group, the GH subgroup showed a significantly higher pregnancy rate compared to the control subgroup (p = 0.043); although the live birth rate was slightly higher, the difference was not statistically significant (p = 0.064). In the <35 years and >40 years groups, no significant differences were observed in pregnancy rate, miscarriage rate, or live birth rate between the GH and control subgroups (p > 0.05). Conclusion GH improves serum oxidative stress and ovarian reactivity in women with PCOS, and increases both the number of oocytes retrieved and the fertilization rate in those aged ≥35 years. Additionally, GH increases the pregnancy rate in PCOS patients aged 35-40 years, although it does not show a significant benefit in live birth rate.

Keywords:  age; growth hormone; in vitro fertilization; ovarian hyperstimulation syndrome; oxidative stress; polycystic ovary syndrome

DOI:  https://doi.org/10.12968/hmed.2025.0546
Adv Biomed Res. 2025 ;14 101

Diving into High Concentration of EGCG: Assessing its Effects on miR-34 and miR-93, PSA, and AR Expression in Prostate Cancer LNCaP Cell Line.

Hossein Mokhtari, Ali Ebrahimi, Parisa Bahavar, Mahdi Bagheri, Mohammad Eavazi, Sara Banihashemi, Yalda Malekzadegan, Zeinab Barartabar.

   Background: Increased miR-93 and decreased miR-34a expressions have been shown in prostate cancer (PC). Prostate-specific antigen (PSA) and androgen receptor (AR) exert a significant role in the onset and progression of PC. This research tried to investigate the effect of EGCG on the expression of miR-34 and 93 and the expression of PSA and AR in PC cell lines.
Materials and Methods: The effect of 5, 20, and 40 µg/ml concentrations of EGCG on the expression of miR-34a and miR-93 on the LNCaP cell line was evaluated through RT-PCR. LNCaP cells were treated with a miR-34a mimic and a miR-93 inhibitor combined with 40 µg/ml of epigallocatechin-3-gallate (EGCG) and then assessed gene expressions using real-time analysis. Cell migration was investigated by scratch assay.
Results: At concentrations of 5 and 20 µg/ml EGCG, the miR-34a and miR-93 expression levels exhibited a reduction compared to the control cohort. Conversely, at a concentration of 40 µg/ml EGCG, there was a notable elevation in the expression levels of miR-93 and miR-34a compared to the control group. Furthermore, a combination of high concentration of EGCG with a miR-34a mimic and miR-93 inhibitor led to a significant change in the expression of PSA and AR in contrast to the EGCG group.
Conclusion: Given the potential cytotoxicity of high concentrations of EGCG toward cancer cells and the conceivable impact on nonmalignant cells, it is imperative to approach its consumption with greater care.

Keywords:  Androgen receptor; epigallocatechin gallate; microRNAs; prostate cancer; prostate-specific antigen

DOI:  https://doi.org/10.4103/abr.abr_193_24
Front Endocrinol (Lausanne). 2025 ;16 1613334

Endometriosis-associated infertility: Multi-omics insights into pathogenesis and precision therapeutics.

Yuyi Ou, Hao Wang, Cankun Zhou, Yonglian Chen, Jun Lyu, Minqing Feng, Xiaobin Huang.

   Introduction: Endometriosis is a prevalent, estrogen-dependent, inflammatory disease that impairs fertility via hormonal dysregulation, immune dysfunction, oxidative stress/ferroptosis, genetic and epigenetic alterations, and microbiome imbalance. We summarize multi-omics insights and clinical implications for endometriosis-associated infertility.
Methods: This article is a Systematic Review that synthesizes recent multi-omics and clinical evidence on mechanisms (hormonal, immune-inflammatory, oxidative stress/ferroptosis, genetic/epigenetic, microbiome/metabolic) and appraises therapeutic strategies spanning surgery, hormonal suppression, assisted reproductive technologies (ART), and emerging adjuncts. Mechanistic and clinical findings are integrated to map targets, biomarkers, and precision-care opportunities across disease phenotypes.
Results: Evidence indicates local estrogen dominance with progesterone resistance, pervasive immune dysregulation, and oxidative stress with iron-driven ferroptosis that particularly injures granulosa cells, alongside disease-relevant genetic/epigenetic regulators and reproductive-tract/gut microbiome dysbiosis. Clinically, endometriosis detrimentally affects ovarian reserve and oocyte competence, disrupts endometrial receptivity/decidualization, and remodels pelvic anatomy through adhesions and fibrosis, cumulatively reducing fecundity. Current management includes laparoscopic excision/ablation, hormonal suppression (e.g., progestins, GnRH analogs/antagonists), and ART tailored to goals and disease severity. Adjunctive antioxidant and immune-modulating approaches show promise but require robust clinical validation. Biomarker discovery-including epigenetic regulators and microbiome-derived signals-may enable earlier diagnosis and personalization. Innovative avenues include immunotherapy targeting nociceptor-immune crosstalk, ferroptosis modulation, microbiota manipulation, and diet-based metabolic strategies.
Discussion: The pathogenesis of endometriosis-associated infertility is multifactorial and interconnected. While current treatments offer benefits, their efficacy is variable. The integration of multi-omics data is unveiling novel diagnostic biomarkers and therapeutic targets. Future management requires a patient-centered, multidisciplinary precision medicine approach that combines mechanistic insights with individualized treatment strategies to improve reproductive outcomes across the disease spectrum.

Keywords:  endometriosis; hormonal dysregulation; immune dysfunction; infertility; microbiome; oxidative stress; therapeutic strategies

DOI:  https://doi.org/10.3389/fendo.2025.1613334
J Chem Inf Model. 2025 Oct 20.

Assessment of the Binding Patterns for Endocrine Disrupting Chemicals in Complex with Estrogen and Androgen Receptors by Leveraging the Asclepios Enalos KNIME Nodes.

Haralampos Tzoupis, Michail Papadourakis, Konstantinos D Papavasileiou, Oliver Burk, Volker M Lauschke, Andreas Tsoumanis, Georgia Melagraki, Antreas Afantitis.

Endocrine disrupting chemicals (EDCs) have been shown to mediate metabolic disruptions in human cells and have been associated with severe adverse health effects. By antagonizing the hormones that act on nuclear hormone receptors, like the estrogen receptor α (ERα) and the androgen receptor (AR), these chemicals disrupt the regulation of various biochemical processes, thereby adversely affecting metabolic homeostasis. The expression of estrogen and androgen receptors in the liver and pancreas, which play an important role in lipid and glucose homeostasis regulation, has made them prime targets affected by EDCs. The different chemical structures of EDCs impose limitations on elucidating their binding mechanisms in nuclear receptors. In this context, in silico tools are able to highlight the potential interactions between the chemicals and the receptors. The aim of this study is to apply molecular simulation and experimental techniques to identify common patterns in the binding process of selected EDCs to ERα and AR and, thus, pinpoint key elements that could be characterized as molecular initiating events (MIE). MM-GBSA and alchemical relative binding free energy (RBFE) calculations have verified the trends observed in the experimental assays regarding the binding affinity of bisphenol compounds. The findings that confirm the agreement between computational and experimental methods offer a framework for future studies on the behavior of EDCs with other metabolically relevant receptors.

DOI: https://doi.org/10.1021/acs.jcim.5c01437
Reprod Sci. 2025 Oct 21.

IL-6 Inhibits Invasion in a Murine Model of Endometriosis.

Eric Han, Ramanaiah Mamillapalli, E Cansu Cevik, Nimisha Gawde, Karenna Thomas, Hugh S Taylor.

  Endometriosis is a gynecological inflammatory disorder characterized by the presence of endometrial tissue outside of the uterus. It affects 10-15% of reproductive aged women, causing pelvic pain and infertility. Existing treatments for endometriosis, including invasive and non-invasive therapies, are plagued by treatment resistance and adverse effects. Dissecting molecular mechanisms or signaling pathways that are involved in the pathophysiology of endometriosis may reveal new molecular targets. IL-6 is classically considered an inflammatory cytokine that is highly expressed in endometriosis. Here, we studied the effect of an anti-IL-6R antibody that interferes with the IL-6 signaling pathway in endometriosis. Endometriosis was induced in c57BL/6 female mice that were subsequently treated with either a murine-specific anti-IL-6 receptor monoclonal antibody (15A7) or IgG2b as a control. We found that there was no change in endometriosis lesion number or volume. However, we observed that the lesion attachment to underlying peritoneum was significantly increased after treatment with the 15A7 antibody, indicating a possible effect on invasion. As expected, IL-6 mediated pathways of p38 MAPK and STAT3 in JAK/STAT signaling were decreased in the anti-IL-6R treatment group compared to isotype control group. There were no differences in N-Cadherin and ICAM between groups. IL-6 had a paradoxical role in endometriosis - preventing or limiting invasion and adhesion.

Keywords:  Endometriosis; IL-6 receptor monoclonal antibody; Mice; Tocilizumab

DOI:  https://doi.org/10.1007/s43032-025-01984-7
ACS Infect Dis. 2025 Oct 24.

The Role of the Microbiome in the Resolution of Infection-Induced Inflammation.

Kerry McGowen, Junhee Lee, Virginia A Pedicord.

  The host microbiome plays a crucial protective role against pathogenic infections, not only through direct competition with invading pathogens but also by coordinating host antimicrobial and barrier functions and educating immune cells. While essential for pathogen clearance, unchecked, prolonged, or excessive inflammation from host immune responses can paradoxically lead to serious consequences for the host including the development of chronic inflammatory and autoimmune diseases. Recent research highlights how microbiome disruptions can exacerbate infection-associated inflammation and pathology. Even with established links among microbes, inflammation, and infection susceptibility, a comprehensive understanding of the cellular and molecular mechanisms connecting the microbiome's role in resolving infection-associated inflammation remains largely undefined. This review discusses our current understanding of the microbiome's contribution to resolving inflammation and tissue damage postinfection and its potential impact on therapeutic approaches for alleviating infection-induced inflammatory diseases.

Keywords:  immunity; infection; inflammation resolution; microbiome; tissue repair

DOI:  https://doi.org/10.1021/acsinfecdis.5c00668
Acta Oncol. 2025 Oct 19. 64 1420-1429

Natural killer cell activity in prostate cancer patients treated with curative radiotherapy with or without androgen deprivation therapy: an observational study.

Stine V Eriksen, Christine V Madsen, Signe Timm, Ahmed H Zedan, Louise Raunkilde, Torben F Hansen, Line Nederby.

BACKGROUND AND PURPOSE: Natural killer (NK) cells play an important role in defense against cancer. Low NK cell activity (NKA) has been linked to prostate cancer (PCa) detection, and effective NKA may be associated with better prognosis in metastatic PCa. Radiotherapy (RT) could affect the immune response, but data on NKA in patients with PCa receiving RT ± androgen deprivation therapy (ADT) remain limited. Hence, this study investigated NKA in such patients. Patient/material and methods: Peripheral blood from 150 patients with PCa receiving curatively intended RT was collected into NK Vue® tubes prior to RT (baseline, BL), after end of RT (EOT), and during follow-up. Patients received 0- (n = 15), 6- (n = 23), or 36-months of ADT (n = 112), starting 3 months before RT. Interferon-γ was a surrogate marker for NKA in NK Vue® tubes. Data were analyzed using descriptive statistics.
RESULTS: Baseline characteristics were similar between patients with normal (≥ 250 pg/mL) (n = 46) and low (< 250 pg/mL) (n = 104) NKA; however, smoking was more prevalent in the low NKA group (28% vs. 11%). The distribution of NKA levels differed between groups and time points, notably showing a decreased interquartile range (IQR) for all groups at EOT (BL median 832 pg/mL, IQR 2901; EOT median 312 pg/mL, IQR 708). NKA fluctuated during follow-up and did not mirror prostate-specific antigen dynamics.
INTERPRETATION: Patients with localized PCa treated with RT ± ADT displayed marked variation in NKA, including treatment-related dynamics. The overall complexity and heterogeneity of NKA raise questions about its clinical utility as a biomarker in this setting.

DOI: https://doi.org/10.2340/1651-226X.2025.44007
J Med Virol. 2025 Nov;97(11): e70654

Sexual Dimorphism in Systemic Inflammatory Responses to Femur Fracture in Mice Infected With SARS-CoV-2-Like Virus.

Matthew D Patrick, Austin Foster, Arun Aneja, Ramkumar T Annamalai.

  Patients with femur fractures who are concurrently infected with COVID-19 face a threefold increase in mortality, likely due to a compounded inflammatory response. Furthermore, sex-specific differences in immune responses to COVID-19 are well documented, implicating biological sex as a factor that can modulate disease severity in these comorbid conditions. Understanding the inflammatory interplay underlying this association is critical for the development of effective, targeted therapies to mitigate mortality. In this study, we investigated the systemic, sex-specific inflammatory response in mice that sustain a fracture while infected with a murine coronavirus (MHV), which belongs to the same genus as SARS-CoV-2. The combined inflammatory insults of MHV infection and fracture (MHV + FX) disrupted systemic immunity in both females and males, producing immune dysregulation characterized by altered cell recruitment and a perturbed inflammatory cascade. In the MHV + FX group, females showed recovery toward a cytotoxic T cell dominant profile by Day 7, whereas males exhibited persistent cytotoxic T cell suppression with relatively higher T helper cells. Cytokine patterns were also sexually dimorphic: females displayed sustained increases in IL-18 and TNF-α in the MHV + FX group alone, whereas males showed distinct modulation of IL-2/IL-2R and transient changes in chemokines such as CCL7 and IL-4 in both the MHV and MHV + FX groups. Notably, these differences were minimal or moderate in control or fracture alone groups. Our findings indicate that sex-divergent immune programs under a dual viral-trauma insult, marked by cytotoxic vs helper T-cell biases and distinct cytokine signatures, help explain the heightened risk when COVID-19 and fractures coincide. These insights support sex-aware immunomodulatory strategies to improve outcomes for COVID-19 patients with musculoskeletal trauma.

Keywords:  Covid‐19; MHV; SARS‐CoV‐2; bone; comorbidity; fracture; trauma

DOI:  https://doi.org/10.1002/jmv.70654
Front Cell Infect Microbiol. 2025 ;15 1658249

Unraveled role of TLR7-mediated interferon signaling activation in COVID-19.

Junjian Xue, Xiaoyin Wang, Hui Wang, Bin Qiao, Pengfei Gao, Bin Ren, Shushan Yan.

  Emerging evidence underscores the critical role of Toll-like receptor 7 (TLR7)-mediated interferon (IFN) signaling in host defense against viral infections including SARS-CoV-2, through the modulation of both innate and adaptive immunity. However, the specific mechanisms by which TLR7 activation shapes SARS-CoV-2-specific immune responses, particularly via IRF-IFN pathways, remain incompletely elucidated. This review synthesizes current findings on how intrinsic TLR7-driven IFN signaling influences viral clearance, modulates adaptive immunity, and contributes to autoantibody production in COVID-19. A deeper understanding of these processes is essential for developing targeted therapeutic interventions and improved vaccines aimed at mitigating severe COVID-19 and preventing post-acute sequelae of SARS-CoV-2 infection (PASC).

Keywords:  B cell immunity; SARS-CoV-2; T cell immunity; interferon; post-acute sequelae of SARS-CoV-2 infection; toll-like Receptor 7

DOI:  https://doi.org/10.3389/fcimb.2025.1658249
Immunobiology. 2025 Oct 20. pii: S0171-2985(25)00262-1. [Epub ahead of print]230(6): 153128

Sexual dimorphism in neutrophil function: Unveiling the discriminative nature of male and female neutrophils.

Richard F Kraus, Nina Doblinger, Michael A Gruber, Maria S Wagner, Johanna Rosenberger.

   BACKGROUND: Women and men are different on many biological levels. Mounting evidence is now recognized that even the immune system has some significant sex differences, which are mainly cell mediated. This study investigated sex-specific differences in function and regulation of polymorphonuclear neutrophil granulocytes (PMNs) in male and female healthy human donors to gain a deeper understanding of the immune response and potential sex-specific dimorphism in immunology.
METHODS: PMNs were obtained from whole blood samples of healthy female and male donors by leuko-/lymphospin density centrifugation. Chemotaxis assays using μ-slide chemotaxis chambers were performed, in which N-formylmethionin-leucyl-phenylalanine (fMLP) stimulated PMNs migrated through a type I collagen matrix. We measured the production of reactive oxygen species (ROS), the release of myeloperoxidase (MPO), and the formation of Neutrophil Extracellular Traps (NETs). Additionally, a flow cytometry assay was conducted to examine functional variations of neutrophil surface markers CD62L, CD11b, and CD66b, as well as the oxidative burst in PMNs obtained from male and female donors.
RESULTS: Sex specific differences of neutrophil function could be determined. Male-derived PMNs initially migrated further distances, while female-derived PMNs showed more targeted movement. However, as the observation period progressed, male-derived PMNs began to exhibit more targeted migration, maintaining straightness towards the end. Differences in neutrophil surface marker expression were observed, with greater levels of CD11b and CD66b on male-derived PMNs after 2 h resting. The different immune effects between the sexes were seen in live cell imaging as well as in flow cytometry analyses.
CONCLUSION: The study revealed significant functional differences between PMNs from male and female donors. To gain reliable results in future PMN studies, it is crucial to consider the sex of the donor.

Keywords:  Chemotaxis; Epitopes; Neutrophil function; Sex; Sexual dimorphism

DOI:  https://doi.org/10.1016/j.imbio.2025.153128
Hum Pathol. 2025 Oct 22. pii: S0046-8177(25)00243-6. [Epub ahead of print] 105956

Loss of androgen receptor expression is associated with aggressive tumor features and reduced survival in breast cancer patients.

Ingunn M Stefansson, Gøril Knutsvik, Jarle Arnes, Karin Collett, Cecilie Askeland, Lars A Akslen.

  Androgen receptor (AR) is reported to be expressed in the majority of breast cancers (BC) with different expression rates across breast cancer subtypes. AR might influence cell proliferation, DNA damage repair, apoptosis, cellular migration and metastasis. The prognostic role of AR varies significantly across breast cancer subtypes. Here, we studied the expression pattern and prognostic relevance of AR in BC, with special focus on molecular stratification. We analyzed a large population-based cohort of breast carcinomas with long and complete follow up. AR expression was evaluated by immuno-histochemistry on tissue microarray slides. Loss of AR was significantly associated with features indicative of poor prognosis (larger tumor diameter, higher histologic grade, estrogen (ER) and progesterone hormone (PR) receptor negativity, elevated proliferation by Ki67, and expression of basal markers). Also, expression of AR was associated with lower proliferation by Ki67 regardless of ER-status. Regarding survival, loss of AR was significantly correlated with decreased breast cancer-specific survival in univariate analysis, both in the overall cohort and within the Luminal A and basal-like (CK5/6+) subgroups. In summary, AR expression emerged as a favorable prognostic factor in breast cancer, demonstrating independent prognostic significance within the basal-like (CK5/6+) subgroup.

Keywords:  Androgen receptor; breast cancer; immunohistochemistry; survival

DOI:  https://doi.org/10.1016/j.humpath.2025.105956
Am J Reprod Immunol. 2025 Nov;94(5): e70180

Immunological Dynamics in PCOS T Cell Exhaustion TIGIT Upregulation Regulated by METTL3-Mediated N6 RNA Methylation.

Zhaowei Cai, Rongju Liu, Li Zhao, Liling Zhou, Qingyang Li, Hongmei He.

   PROBLEM: Polycystic ovary syndrome (PCOS) stands as a multifaceted endocrine disorder with implications beyond reproductive health, encompassing metabolic and immunological dimensions. This study delves into the immunological alterations within T cells in a murine PCOS model, unraveling novel insights into the molecular mechanisms contributing to T cell dysfunction.
METHOD OF STUDY: A PCOS model was established in mice, followed by isolating T cells. Isolated T cells were activated by anti-CD3 and anti-CD28 antibodies. Cytokine levels were determined by enzyme-linked immunosorbent assay (ELISA) assay, and carboxyfluorescein succinimidyl ester (CFSE) dye was utilized for proliferation detection. Flow cytometry was utilized for analyzing exhaustion markers. RNA methylation analysis was determined by methylated RNA immunoprecipitation (Me-RIP) assay.
RESULTS: In the PCOS mouse model, T cells exhibited a state of exhaustion, including impaired activation, reduced cytokine secretion, and decreased proliferative capacity. Particularly, the expression of T cell immunoreceptor with Ig and ITIM domain (TIGIT) molecules on the surface of T cells was significantly increased, which was associated with T cell exhaustion. The stability of TIGIT mRNA was enhanced due to the increased level of N6 RNA methylation, in which the methyltransferase-like 3 (METTL3) methyltransferase played a key role. Experiments showed that by inhibiting N6-methyladenosine (M6A) methylation or knocking out METTL3, the activation phenotype of PCOS T cells could be reversed, and cytokine secretion and proliferative capacity could be restored.
CONCLUSIONS: Although acknowledging study limitations, such as the murine model's partial recapitulation of human PCOS complexity, this research provides a foundation for future investigations into the specific molecular mechanisms governing T cell function and potential therapeutic targets within the N6 RNA methylation pathway.

Keywords:  METTL3; N6 RNA methylation; T cell exhaustion; TIGIT; polycystic ovary syndrome (PCOS)

DOI:  https://doi.org/10.1111/aji.70180
Reprod Fertil Dev. 2025 Oct 23. pii: RD25081. [Epub ahead of print]37(16):

Data-driven biomarker discovery and risk profiling for polycystic ovary syndrome in Indian women using ensemble learning.

Pulkit Verma, Rekha Agarwal, Lokesh Kumar Sharma, Nidhi Sindwani.

   CONTEXT: Despite diagnostic advancements in India, the scarcity of Indian polycystic ovary syndrome (PCOS) data and varied diagnostic standards contribute to delays in PCOS detection, particularly in rural areas.
AIMS: We aim to build a predictive model based on an extensive dataset derived from Indian studies and perform risk-based stratification of samples.
METHODS: The PubMed database was queried for studies focused on the pathophysiology of PCOS in Indian women. Based on inclusion and exclusion criteria, six studies were selected. Corresponding clinical data was statistically synthesised based on study-specific baseline characteristics. The integrated dataset consisted of 11,258 samples (nPCOS = 7342; nControl = 3916) with 14 attributes: disease (PCOS vs control), age, body mass index, cholesterol, triglycerides, high-density and low-density lipoproteins, LH, FSH, testosterone, menarche age, systolic and diastolic blood pressure, and yearly menstrual cycles. After data pre-processing, missing values imputation, and feature engineering, model benchmarking was conducted using LazyPredict. LightGBM was selected for further hyperparameter tuning based on performance metrics. Lastly, feature importance analysis was performed, and predictive probabilities were utilised to categorise samples into different risk categories.
KEY RESULTS: The optimised LightGBM model achieved 96.18% accuracy, 97.51% precision, 96.65% recall, and 99.31% receiver operating characteristic area under curve (ROC-AUC) score. Further, testosterone, menstrual cycles per year, triglycerides, LH, and diastolic blood pressure were the top five key attributes in PCOS. Risk categorisation of samples demonstrated substantial alignment with real diagnoses, validating the model's clinical significance.
CONCLUSIONS: This study introduces the first comprehensively synthesised PCOS dataset for Indian women.
IMPLICATIONS: Our framework facilitates prompt risk detection, providing an adaptable methodology for decision-making in PCOS management.

Keywords:  Indian reproductive health; PCOS; Polycystic Ovary Syndrome; ensemble learning; machine learning; predictive modeling; reproductive disorders; risk stratification

DOI:  https://doi.org/10.1071/RD25081
Nat Biomed Eng. 2025 Oct 23.

Collagen-binding IL-12-armoured STEAP1 CAR-T cells reduce toxicity and treat prostate cancer in mouse models.

Koichi Sasaki, Vipul Bhatia, Yuta Asano, Jakob Bakhtiari, Pooja Kaur, Chuyi Wang, Takumi Matsuo, Olivier Dubois, Po-Chuan Chiu, Donny Gun, Charanjit Singh, Ioanna Panagi, Laurine Noblecourt, Maria Nikolaidi, Truman Chong, Gerardo Javier, Saul J Priceman, Aude G Chapuis, John K Lee, Jun Ishihara.

Immunosuppressive microenvironments, the lack of immune infiltration, and antigen heterogeneity pose challenges for chimaeric antigen receptor (CAR)-T cell therapies applied to solid tumours. Previously, CAR-T cells were armoured with immunostimulatory molecules, such as interleukin 12 (IL-12), to overcome this issue, but faced high toxicity. Here we show that collagen-binding domain-fused IL-12 (CBD-IL-12) secreted from CAR-T cells to target human six transmembrane epithelial antigen of prostate 1 (STEAP1) is retained within murine prostate tumours. This leads to high intratumoural interferon-γ levels, without hepatotoxicity and infiltration of T cells into non-target organs compared with unmodified IL-12. Both innate and adaptive immune compartments are activated and recognize diverse tumour antigens after CBD-IL-12-armoured CAR-T cell treatment. A combination of CBD-IL-12-armoured CAR-T cells and immune checkpoint inhibitors eradicated large tumours in an established prostate cancer mouse model. In addition, human CBD-IL-12-armoured CAR-T cells showed potent anti-tumour efficacy in a 22Rv1 xenograft while reducing circulating IL-12 levels compared with unmodified IL-12-armoured CAR-T cells. CBD fusion to potent payloads for CAR-T therapy may remove obstacles to their clinical translation towards elimination of solid tumours.

DOI: https://doi.org/10.1038/s41551-025-01508-3