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Mare endometrosis is a chronic degenerative condition of the endometrium, primarily characterized by fibrosis, involving interactions among fibroblasts, immune cells, and epithelial cells regulated by cytokines and growth factors. T helper (Th)1 and Th2 cells seem to play a pivotal role in fibrosis. However, their roles in equine endometrial fibrosis remain unknown. This study explores Th1 and Th2 cell distribution across different stages of endometrium histopathological Kenney and Doig categories; and evaluated their secretome effects on non-fibrotic endometrium derived fibroblast functional characteristics, extracellular matrix (ECM)-associated mRNA transcription, and transcriptomic profiles. Th1 and Th2 cells, along with cytokines (IFN-γ, IL-4, IL-13) and their receptors, were present in mare endometria at all endometrium stages. Th1 secretome influenced genes enriched in metabolism, cell cycle, and ECM-related pathways, while Th2 secretome regulated genes enriched in tissue remodeling and signaling pathways, suggesting their role in the development of fibrosis in the endometrosis progression.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-025-20152-0.

T cell-based immunotherapies hold promise in treating cancer by leveraging the immune system’s recognition of cancer-specific antigens1. However, their efficacy is limited in tumours with few somatic mutations and substantial intratumoural heterogeneity2–4. Here we introduce a previously uncharacterized class of tumour-wide public neoantigens originating from RNA splicing aberrations in diverse cancer types. We identified T cell receptor clones capable of recognizing and targeting neoantigens derived from aberrant splicing in GNAS and RPL22. In cases with multi-site biopsies, we detected the tumour-wide expression of the GNAS neojunction in glioma, mesothelioma, prostate cancer and liver cancer. These neoantigens are endogenously generated and presented by tumour cells under physiologic conditions and are sufficient to trigger cancer cell eradication by neoantigen-specific CD8+ T cells. Moreover, our study highlights a role for dysregulated splicing factor expression in specific cancer types, leading to recurrent patterns of neojunction upregulation. These findings establish a molecular basis for T cell-based immunotherapies addressing the challenges of intratumoural heterogeneity. A study identifies public neoantigens generated by tumor-wide aberrant mRNA splicing activity across distinct cancer types.

The ion channel-kinase TRPM7 maintains intracellular Mg2+ homeostasis, affects early Ca2+ signals, influences downstream Ca2+-dependent signaling pathways and thus is crucial for T-cell activation and differentiation. By modulating AKT/SMAD2 signaling, TRPM7 acts as a molecular switch to balance Treg/TH17 polarization. T-lymphocyte activation is a crucial process in the regulation of innate and adaptive immune responses. The ion channel-kinase TRPM7, transient receptor potential cation channel subfamily M, member 7, has previously been implicated in cellular Mg2+ homeostasis, proliferation, and immune cell modulation. Here, we show that pharmacological and genetic silencing of TRPM7 leads to diminished activation and influences signaling pathways that guide human TH17 or Treg cell differentiation, following TCR-mediated stimulation. In primary human CD4 T cells and CRISPR-Cas9-engineered Jurkat T cells, inactivation or loss of TRPM7 led to distorted Mg2+ homeostasis and Ca2+ signaling, reduced NFAT translocation, decreased IL-2 secretion and altered TH cell differentiation. While the activation of primary human CD4 T cells, as well as in vitro polarization into pro-inflammatory TH17 cells was critically dependent on TRPM7, the polarization of naïve CD4 T cells into FOXP3+ regulatory T cells was not. Taken together, these results highlight TRPM7 as molecular switch in lymphocyte activation and polarization. Thus, suggesting a therapeutic potential for TRPM7 in numerous T-cell mediated diseases.