Neoadjuvant immunochemotherapy (nICT) has emerged as a promising neoadjuvant strategy for esophageal squamous cell carcinoma (ESCC). Identification of the factors affecting the responsiveness to nICT could help further improve treatment efficacy. Here, we performed single-cell analysis on 14 ESCC patients undergoing nICT and revealed tumor microenvironment (TME) features associated with differential treatment responses. Nonnegative matrix factorization (NMF) identified five coordinated cellular programs with distinct response associations. Specifically, the NMF3 program mainly comprising immunosuppressive cell subsets was enriched in the minimal or no pathological tumor regression (TRS3) group, in which regulatory T cells (Tregs) and dendritic cells (DCs) exhibited close correlation. In addition, elevated expression of mitochondrial transcription factor A (TFAM) in DCs was associated with increased Treg infiltration in the TRS3 group. A myeloid-specific Tfam knockout mouse model showed that TFAM deficiency reversed the immunosuppressive TME, inhibited tumor growth, and enhanced response to anti-PD-1 therapy in ESCC. Mechanistically, TFAM deficiency in DCs activated the STING-TBK1-IRF3 pathway, thereby promoting DC maturation to enhance anti-tumor immunity. Overall, this study characterized the TME in residual ESCC after nICT and revealed an association between elevated TFAM expression in DCs and poor responsiveness to nICT. These findings indicate the critical role of TFAM deficiency in DCs in activating anti-tumor immunity, highlighting the potential of targeting TFAM to improve the efficacy of immunotherapy and optimize therapeutic strategies.

Sexual intercourse is associated with recognition of partner-derived major histocompatibility complex (MHC) and minor histocompatibility alloantigens (MiHAs) by females. Male sperm-associated MHC antigens, expressed on spermatozoa and leukocytes, as well as MiHAs including sperm-specific antigens (SPAGs), are recognized by female T lymphocytes infiltrating the cervicovaginal region. This can occur via direct presentation of male MHC molecules on male antigen presenting cells and indirect presentation of male antigen peptides (MHC and MiHAs) bound to female MHC molecules on female antigen presenting cells. This process along with the presence of anti-inflammatory chemokines and cytokines and sHLA-G present in seminal fluid leads to activation of male antigen-specific FOXP3+ Treg locally and in regional lymph nodes. This regulatory response has been shown to promote survival and progression of spermatozoa within the cervical mucus as well as implantation of the embryo. Most important, it is believed to set the stage for fetal-maternal tolerance during pregnancy. Conversely, under certain circumstances, alloresponses to male antigens can lead to the production of anti-MHC and anti-sperm-specific antigens antibodies resulting in infertility. Altogether, these observations show that alloimmunity induced after sexual intercourse plays an essential role in reproduction. In addition, while the influence of pregnancy in transplantation is well established, some studies suggest that repeated sexual exposure to male antigens can increase the risk of solid organ transplant rejection.

Airway epithelial cells (AEC) are the primary sources of Semaphorin3E (Sema3E) in human airways and its expression is downregulated in severe asthmatics, underscoring the AEC-derived Sema3E critical role in lung homeostasis. Here, we investigated the effects of AEC-derived Sema3E on immune responses in an acute house dust mite (HDM) asthma model. Transgenic Sema3E overexpression in AECs, using tamoxifen-inducible Scgb1a1Cre, did not alter lung neutrophils, eosinophils, macrophages, dendritic cells, B cells, and CD4 T-cell number and BALF cytokine levels. However, it significantly increased lung Foxp3+ Treg cell number and proliferation. To assess the role of Sema3E-plexinD1 signaling in Foxp-3 cells, cell-specific Foxp3-PLXND1 knockout (KO) mice were subjected to HDM exposure. These mice exhibited reduced Foxp3+ Treg cell numbers in the lungs, spleen, and mediastinal lymph nodes, accompanied by increased lung eosinophil infiltration, elevated IFN-γ+ CD4+ T cells in the spleen, and higher BALF levels of IL-17, IL-5, and CXCL8. Foxp3 PLXND1 deficiency also enhanced the number of T follicular helper cells, germinal center B cells, and IgG1/IgE antibodies in sera. Additionally, Muc5AC gene expression and goblet cell hyperplasia were elevated in Foxp3PLXND1 KO mice. These findings highlight the Sema3E-plexinD1 axis as a key regulator of Treg cell-mediated immune homeostasis, suggesting its therapeutic potential in asthma.

Endometriosis is a chronic, heterogenous disorder in which cyclical hemorrhage and repetitive repair generate ectopic implants that persist, recur, and drive pain and infertility; conventional frameworks emphasizing hormonal aberration and immune failure incompletely explain lesion fibrotic maturation and spatial heterogeneity. We synthesize human, experimental, and emerging spatial-omic evidence to advance a unifying mechanistic paradigm: cyclical bleeding seeds an immunothrombotic niche in which activated platelets and fibrin scaffolds organize immune cells and stromal responders, and platelet-derived signals, including P-selectin, TGF-β and platelet-derived microparticles (PMPs), act as upstream instructors of both immune dysregulation and fibrogenic stromal reprogramming. Quantitative histology and SHG imaging demonstrate spatial platelet hotspots that co-localize with NK suppression, CD163+ macrophage polarization and aligned collagen bundles in human lesions, while PMP proteomics and functional uptake assays link vesicular cargo to myofibroblast and reparative macrophage transcriptional programs. Mechanistically, platelet TGF-β and PMP cargo downregulate NK effector receptors (for example NKG2D), reprogram macrophages toward LOX-enriched matrix-remodeling states, and bias adaptive responses toward tolerance (Treg/Th17 imbalance), creating microdomains permissive for lesion survival. These processes engage a mechanobiological feedback loop: LOX-dependent collagen crosslinking increases stiffness, which amplifies myofibroblast and immune phenotypes and further recruits platelets, consolidating fibrotic architecture. We propose a research and translational roadmap, standardized PMP pipelines, integrated scRNA/spatial cohorts, ex vivo perturbations, and early proof-of-concept trials targeting adhesion (P-selectin), PMP biology, TGF-β activation or LOX, to test causality and enable precision interventions for the "immunofibrotic" endometriosis phenotype. Reframing endometriosis as a platelet-organized immunofibrotic disorder identifies novel druggable nodes and biomarker strategies with immediate potential to change both mechanistic research and clinical management.

Periodic activation of regulatory T cells (Tregs) is necessary to restrict autoreactive T cells and maintain immune homeostasis. IL-2-STAT5 signaling instructs several metabolic processes underlying Treg activation, including the mevalonate pathway, which is crucial for optimal Treg responses. However, direct links between IL-2-STAT5, mevalonate, and Treg function have yet to be established. To explore this relationship, we deleted sterol regulatory binding element protein 2 (Srebp2), a critical mediator of mevalonate metabolism, selectively in Tregs. Here, we show that when Srebp2-deficient Tregs are placed under physiological stress by competing with wild-type Tregs, the former exhibit impaired proliferation, survival, and activation. RNA sequencing of Tregs in this competitive setting demonstrate that Srebp2 contributes to pathways controlling IL-2R signaling, cholesterol homeostasis, activities associated with the mevalonate pathway, and expression of genes associated with activated Tregs. These findings link Srebp2, the IL-2R, and the mevalonate pathways for efficient Treg homeostasis and activation. These effects, however, require a competitive setting, as mice with only Srebp2-deficient Tregs were outwardly normal with respect to their development, homeostasis, metabolic activity, and function. Thus, Srebp2 is necessary to optimally tune Treg homeostasis and activation, but sufficient redundancy exists to compensate for the lack of Srebp2 to maintain Treg development and function in the absence of physiological stress.

The 2025 Nobel Prize in Physiology or Medicine was awarded jointly to Mary Brunkow, Fred Ramsdell and Shimon Sakaguchi for characterizing regulatory T cells (Tregs) and identifying the FOXP3 gene as their "master regulator". This work rehabilitated the long-debated concept of suppressor T cells, and established the field of peripheral immune tolerance. Beyong recounting the historical contributions of the laureates, this article reviews the emergence of Treg research in France since the early 2000s, highlighting the decisive influence of Benoît Salomon in the establishment and development of this field at the national level.

Radiation-induced lung injury (RILI) constrains thoracic radiotherapy dosing and includes acute radiation pneumonitis (RP) and chronic radiation-induced pulmonary fibrosis (RPF). This narrative review explores the gut-lung microbiota axis in RILI, synthesizing evidence from preclinical models, clinical cohorts (N = 52-89), and randomized controlled trials (RCTs). Radiotherapy induces gut dysbiosis, barrier breakdown, and metabolite changes [e.g., short-chain fatty acid (SCFA) and desaminotyrosine (DAT) depletion], promoting inflammation and fibrosis via pathways such as Toll-like receptor 4/nuclear factor kappa B (TLR4/NF-κB), TGF-β/Smad, sphingosine-1-phosphate (S1P)-S1PR, and cGAS-STING in animal studies. Inter-species microbial variations hinder translation, while lung microbiota shifts remain nascent. In non-small cell lung cancer cohorts, lower gut microbiota stability (a marker of dysbiosis) is associated with an increased risk of grade ≥2 RP (multivariable-adjusted models, p < 0.05), with higher baseline Faecalibacterium abundance conferring protection; however, causality remains unproven due to antibiotic confounding. Mechanisms involve lipopolysaccharide (LPS) translocation, interleukin 25 (IL-25)/S1P-driven type 2 innate lymphoid cell (ILC2) migration, regulatory T cell/T helper 17 cell (Treg/Th17) imbalance, and extracellular vesicle (EV) signaling, with biomarkers such as 16S rRNA sequencing and EV-miRNAs (e.g., miR-486-5p). Artificial intelligence models predict RP with 75% accuracy. Phase-specific interventions, such as pre-radiotherapy gut microbiota monitoring, intra-radiotherapy SCFA supplementation, subacute DAT modulation, and RPF-targeted EV therapies, have been explored in preliminary pilot studies [for example, one small study reported approximately 12% FEV1 improvement following fecal microbiota transplantation (FMT)]. Future large-scale, stratified RCTs that properly account for antibiotics, chemotherapy, and immunotherapy are required to establish causality beyond the current largely associative clinical evidence. The integration of immunotherapy and proton therapy in such trials may help clarify gut-lung interactions, including any microbiota-preserving effects of proton therapy; the role of the lung microbiota in fibrosis remains preliminary.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with limited therapeutic options, in which neuroinflammation critically drives disease progression. Regulatory T cells (Tregs) exert potent immunosuppressive and neuroprotective effects, offering great potential for ALS treatment. However, clinical application of Treg therapy is hampered by low peripheral cell abundance and unstable expansion quality. Here, we established and optimized a GMP-grade protocol for sorting and expanding peripheral blood-derived Tregs, and validated cryopreserved apheresis products as feasikble starting materials. Although ALS patient-derived Tregs showed reduced expansion capacity compared with healthy donor counterparts, they maintained comparable purity, stable regulatory phenotypes, and robust immunosuppressive function. Transcriptomic analysis confirmed the lineage fidelity and low pro-inflammatory characteristics of expanded Tregs. Therapeutic efficacy was verified in SOD1G93A ALS and GvHD mouse models with delayed disease progression and relieved inflammation. This study provides standardized GMP manufacturing strategies and solid preclinical evidence to support the ongoing clinical trial (NCT06671236) and facilitate Treg immunotherapy translation for ALS.

Inositol-trisphosphate 3-kinase A (ITPKA) has been implicated in tumor progression; however, its potential role in clear cell renal cell carcinoma (ccRCC) remains insufficiently defined. This study investigated the expression pattern, prognostic relevance, and potential functional associations of ITPKA in ccRCC. Bioinformatic analyses were performed using TCGA and GEPIA2 datasets to evaluate ITPKA expression, clinicopathological relevance, survival associations, immune infiltration patterns, and enriched signaling pathways. Immunohistochemical (IHC) staining was conducted in 20 paired ccRCC and adjacent non-tumor tissue samples to provide exploratory protein-level validation. Functional assays were performed in 786-O cells following ITPKA knockdown or overexpression. Rescue assays targeting PPAR pathway, using the PPARγ antagonist GW9662 and PPARG overexpression, were used to examine whether PPAR signaling mediates ITPKA-associated cellular phenotypes. ITPKA expression was upregulated in ccRCC tissues and associated with adverse clinicopathological characteristics and unfavorable survival outcomes in the TCGA-KIRC cohort. Exploratory IHC analysis confirmed stronger ITPKA staining in ccRCC tissues than in matched adjacent normal tissues. Immune infiltration analysis suggested a possible association between ITPKA expression and specific immune cell populations, particularly Treg and Th2 cells. In 786-O cells, ITPKA knockdown attenuated malignant cellular phenotypes, including migration and invasion. Rescue assays showed that PPARγ inhibition with GW9662 partially reversed the effects of ITPKA knockdown, whereas PPARG overexpression attenuated the phenotypic changes induced by ITPKA overexpression. However, the present study does not establish a direct biochemical interaction between ITPKA and PPAR pathway components. In conclusion, ITPKA may serve as a potential biomarker and functional regulator in ccRCC. These findings provide preliminary evidence for an ITPKA-PPAR-related regulatory axis and warrant further validation in larger clinical cohorts and additional experimental models.