Tissue-resident memory T cells (TRM), which function against tumors, infections, and non-self antigens in organ transplantation, exhibit both effector and memory functionality. However, the homeostasis and differentiation of TRM is not clear. Using a murine kidney transplant model for long-term observation, our single-cell and spatial transcriptomics showed that CD49a+PD1hi CD8+ TRM exhibited an effector phenotype with enhanced cytotoxicity at a later stage. This subset might mature from a CXCR6hi precursor-like state with proliferation capacity in tertiary lymphoid structures (TLSs) in allografts. Mechanically, BHLHE40 is required for CD49a+PD1hi CD8+ TRM differentiation and effector function, thereby driving rejection in allo-transplantation. In TLSs, TGF-β orchestrated BHLHE40 expression in TRM and effector TRM differentiation. Our findings identified an effector subset of TRM as CD49a+PD1hi CD8+ TRM, and highlighted a BHLHE40-orchestrated, resident immune component, rather than circulating cells, as a major contributor to allograft rejection.

Distinct macrophage activation states play key roles in the formation and progression of heart allograft fibrosis. However, the exact molecular mechanisms that regulate the balance between inflammatory and pro-fibrotic macrophage responses during fibrosis remain poorly understood. Identifying and targeting the key molecule that regulates the differentiation of inflammatory and pro-fibrotic macrophages might be a pivotal strategy for mitigating fibrosis and prolonging allograft survival. Here, using single-cell sequencing analysis of human heart allografts fibrosis patient samples, we identified a population of macrophages that undergo epigenetic reprogramming through DNA methylation regulated by DNA methyltransferase DNMT1. DNMT1 small-molecule inhibitor 5-AzaC significantly attenuated graft fibrosis and prolonged allograft survival by inhibiting both inflammation and excessive tissue repair. Mechanistically, DNMT1-targeted macrophages suppress the DNA methylation level of the CpG island in the first intron of PTPRD, promoting PTPRD expression, which in turn inhibits the activity of STAT3 and STAT6 pathways, thereby suppressing the differentiation of inflammation and pro-fibrotic macrophages. Based on this, we developed a macrophage-targeted nanocarrier, MV/PEG-LPs, to load 5-AzaC, thereby enhancing its therapeutic precision for allograft fibrosis. Our results reveal a novel target, DNA methylation in macrophages, for the treatment of fibrosis-related diseases.

Epigenetic dysregulation is associated with immune evasion and immune checkpoint blockade (ICB) resistance. Here, using in vivo CRISPR/Cas9 screens targeting epigenetics-related factors in mouse tumor models treated with ICB, we identified chromobox 4 (CBX4) as a key negative regulator of the immune tumor microenvironment (TME). Single-cell RNA-seq and spatial transcriptomics analyses of patients receiving neoadjuvant anti-programmed cell death protein 1 (anti-PD-1) therapy revealed high CBX4 expression in both tumor cells and immunosuppressive tumor-associated macrophage subpopulations, with preferential accumulation in nonresponders. Deficiency of CBX4 in macrophages or tumor cells induced robust antitumor immunity and increased infiltration and the cytotoxic activity of CD8+ T cells and NK cells, thereby heightening the sensitivity of ICB treatment. Mechanistically, CBX4 targeted H3K9me3- and H3K27me3-marked endogenous retroelements such as RLTR4-Mm-int. Loss of CBX4 derepressed retrotransposons, activating cytosolic RNA-sensing pathways and triggering the type I IFN response, ultimately leading to a robustly inflamed TME. Moreover, we uncovered a negative correlation between CBX4 expression, immune responses, and retrotransposon levels, and were able to determine the prognosis of patients with hepatocellular carcinoma (HCC) undergoing ICB therapy. Our study establishes CBX4 as an epigenetic immune checkpoint through the epigenetic silencing of retrotransposons, remodeling the immune TME and thus providing a promising therapeutic target to enhance tumor immunogenicity and overcome immunotherapy resistance.

Hereditary multiple osteochondromas (HMO), previously known as hereditary multiple exostoses (HME), is a congenital skeletal developmental anomaly characterized by multiple osteochondromas that commonly grow outward from the metaphyses of long bones. Hereditary multiple exostoses is an autosomal dominant genetic disease characterized by multiple cartilage growth disorders, which affect the long bones of the limbs, scapula, and ribs, among others. Consensus on the diagnosis and treatment of spinal involvement is relatively lacking. For such patients, experience in terms of clinical screening, preoperative evaluation, surgical intervention indications and timing, surgical expertise and lessons learned, and follow-up is needed and critical. This review focuses on the clinical evaluation and orthopedic surgical treatment of HME patients with spinal involvement. It summarizes the patients' diagnosis, clinical features, and treatment strategies based on evidence from the published literature. The clinical manifestations, location of onset, and surgical intervention are summarized in detail in this review. The above contents will help improve the clinical diagnosis and treatment level of HME patients with spinal involvement internationally.

Accessory breast carcinoma represents a distinct ectopic malignancy comprising approximately 0.3-0.6% of all mammary neoplasms, of which male accessory breast cancer is even rarer. This condition typically manifests as a progressively enlarging mass, predominantly situated in the axillary or inguinal regions, and may present with early lymph node metastasis. Pathological examination remains the diagnostic gold standard, whereas ultrasound, mammography, and MRI serve as critical adjunctive modalities. Current therapeutic strategies for accessory breast carcinoma largely mirror established breast cancer protocols, establishing surgical resection as the cornerstone, followed by adjuvant endocrine therapy, chemotherapy, and radiotherapy. Here, we report a case of a 72-year-old male with accessory breast cancer. The patient was diagnosed with right axillary accessory breast cancer with right axillary lymph node metastatic cancer in 2021 and underwent right accessory mastectomy plus right axillary lymph node dissection at our hospital. Postoperatively, the patient completed adjuvant chemotherapy and remains on maintenance endocrine therapy. In 2025, a follow-up examination revealed a new mass in the medial aspect of the right upper arm near the axilla. Histopathological evaluation of the excised specimen confirmed features consistent with mucinous breast carcinoma. This report seeks to heighten clinical vigilance regarding male accessory breast carcinoma by providing a comprehensive delineation of its diagnostic trajectory, clinical progression, and therapeutic management in an exceptionally rare presentation.

Mitochondrial dysfunction is a critical factor driving the exhaustion of tumor-infiltrating CD8+ T cells and impeding the efficacy of tumor immunotherapy. However, the key regulatory proteins and molecular mechanisms governing mitochondrial function in CD8+ T cells remain enigmatic. Here, we report that PARK7 is significantly enriched in the mitochondria of tumor-infiltrating CD8+ T cells. T-cell-specific PARK7 deficiency enhanced mitochondrial function in CD8+ T cells, alleviated T-cell exhaustion, and suppressed tumor growth. Mechanistically, we found that PARK7 directly interacted with the mitochondrial membrane protein ATAD3A and downregulated its lactylation level, thereby suppressing the expression of mitochondrial-related genes and ultimately promoting CD8+ T-cell exhaustion. Overall, our study not only identifies the critical role of PARK7 in regulating mitochondrial function in CD8+ T cells but also elucidates the molecular mechanism through which the PARK7-ATAD3A axis modulates mitochondrial gene expression, providing a potential therapeutic strategy for targeting PARK7 in tumor immunotherapy.

Hematopoietic stem cell transplantation (HSCT) remains an effective treatment for severe aplastic anemia (SAA), but the optimal conditioning regimen has yet to be established. This study aimed to evaluate the safety and efficacy of a conditioning regimen consisting of fludarabine (Flu), cyclophosphamide (Cy), and porcine anti-lymphocyte globulin (p-ATG). This prospective single-arm clinical trial enrolled 48 SAA patients who underwent HLA-matched sibling transplantation. The conditioning regimen consisted of p-ATG (120 mg/kg), Cy (120 mg/kg), and Flu (120 mg/m²). All patients achieved neutrophil engraftment (median time of 12 days), with 98

This study presents a preoperative prediction model for tumor-induced osteomalacia (TIO) surgery outcomes on the basis of patient characteristics. The model, which was validated in 309 patients, identifies key risk factors and aids in clinical decision-making to optimize treatment strategies, reduce the number of unnecessary surgeries, and improve patient care. Tumor-induced osteomalacia (TIO) should be curable by complete removal of the causative tumor. Knowledge of the prognosis of surgery is lacking. This study aimed to establish a prediction model that uses the preoperative characteristics of patients to predict the surgical treatment outcomes of patients with TIO. This was a single-center, retrospective, case-control study. The main outcome was the surgical outcomes of patients with TIO. Patients with TIO who underwent surgical treatment were divided into a training set and a validation set. A nomogram was established in the training set, and the model was evaluated by the C-index, calibration curve, and clinical impact curve and verified in the validation set. A total of 309 patients with TIO were included, with 222 in the training set and 87 in the validation set. The C-index of the nomogram was 0.864 (p < 0.001). The model had high goodness of fit—which is suggested by the calibration curve, and clinical benefit is indicated by the decision curve analysis and clinical impact curve. In the validation set, the area under the curve of the prediction model was 0.782 (p < 0.001), and decision curve analysis and clinical impact curve also suggested the existence of clinical benefit. This study established a prognostic model for the preoperative prediction of surgical outcomes for TIO. This model can be used as a reference in clinical practice for the development of individualized treatment strategies.

Inflammatory myofibroblastic tumor (IMT) is a rare spindle-cell neoplasm. IMT currently suffers from a paucity of standardized diagnostic and therapeutic guidelines. The Chinese expert consensus committee on the diagnosis and treatment of IMT formed an "Expert consensus on the diagnosis and treatment of inflammatory myofibroblastic tumor". This consensus was developed through a comprehensive synthesis of expert opinions, an extensive review of the literature, and a series of offline and online deliberations. The committee aspires that this consensus will enhance the therapeutic outcomes and prognosis for patients with IMT in the future.

The peripheral nervous system (PNS) and immune system are anatomically and cellularly interconnected and function synergistically to maintain organismal homeostasis. Peripheral nerve fibers release neurotransmitters and neuropeptides that modulate the immune microenvironment, thereby influencing disease progression. The emerging field of peripheral neuroimmunology focuses on the intricate communication between PNS and immune responses. In this review, we systematically analyze the molecular mechanisms through which PNS modulates immune cell function. We also summarize recent advances in neuroelectric stimulation and pharmacological strategies targeting the neuroimmune axis for the treatment of various diseases. Our analysis highlights that PNS and immune system share multiple ligands and receptors. These ligands and receptors work in coordination to respond to internal and external challenges and actively influence disease progression. By synthesizing findings on autonomic nervous system (ANS)-mediated immune regulation and sensory neuron-immune communication, we propose a theoretical framework. This framework helps us understand how neuroimmune circuits maintain physiological balance and contribute to disease pathology. This conceptual model offers new perspectives for developing targeted clinical interventions along the neuro-immune axis.

Ischemia-reperfusion injury (IRI) and bile salt toxicity are significant contributors to post-transplant cholangiopathy. Ferroptosis appears to play a critical role in intrahepatic bile duct injury induced by ischemia-reperfusion (I/R) and bile salt toxicity. Our study aimed to elucidate the role of ferroptosis in bile duct injuries and its potential as a therapeutic target for liver diseases. Mouse models of liver ischemia-reperfusion (I/R) and α-naphthyl isocyanate (ANIT)-induced liver cholestasis were employed to investigate the role of ferroptosis in intrahepatic bile duct injury in vivo. Hypoxia-reoxygenation (H/R) and bile salt treatment models were utilized to simulate the post-transplant bile duct injury process in vitro. In mouse models of liver I/R and cholestasis, we observed a downregulation of glutathione peroxidase 4 (GPX4) and an upregulation of lipid peroxidation levels in bile duct cells. Furthermore, the ferroptosis inhibitor Liproxstatin-1 (Lip-1) significantly attenuated intrahepatic bile duct injuries. Ferroptosis inhibitors alleviated cell death and lipid peroxide accumulation in human intrahepatic biliary epithelial cells (HiBECs) subjected to H/R or glycochenodeoxycholate (GCDCA) treatment. GCDCA treatment led to ferroptosis in HiBECs along with ferritin degradation. Inhibition of autophagy alleviated GCDCA-induced bile duct cell death. Our study suggested that ferroptosis played an important role of in the intrahepatic bile duct injury during I/R or cholestasis.

Tissue fibrosis is commonly associated with organ malfunction and is strongly associated with the development of chronic rejection, cardiovascular diseases, and other chronic diseases. Fibrosis also contributes to immune exclusion in tumor tissues. Targeting fibrosis might be a strategy for prolonging allograft survival while suppressing cancer development. Here, single-cell transcriptomes of human and mouse heart allografts showed that macrophages accumulated in grafts with fibrosis were reprogrammed via histone methylation regulated by Setdb1, an H3K9 methyltransferase. Myeloid-specific deletion of Setdb1 prolonged heart allograft survival but reversed immune exclusion in tumor tissues. Interestingly, myeloid-specific Setdb1-knockout led to lower fibrosis in heart allografts and tumor tissues in mice. Our single-cell sequencing data showed that Setdb1 ablation impaired Fn1+ and SPP1+ profibrogenic macrophage reprogramming. Mechanistically, Fn1, which was induced by the CCR2-Creb/Setdb1 axis, upregulated the expression of genes related to fibrosis in fibroblasts and macrophages via ITGA5 and PIRA receptors. Blocking the interaction between FN1 and these receptors inhibited fibrosis in allograft and tumor tissues. Our results reveal a target, histone methylation in macrophages, for the treatment of fibrosis-related disease.

BACKGROUND:Chronic rejection is the leading cause of progressive allograft function decline. Studies have demonstrated that CD40-CD40L-induced paired immunoglobulin-like receptor-A (PIR-A) is the MHC-I receptor necessary for the specific memory response in macrophages of mice with chronic rejection. However, the underlying mechanisms remain unclear. METHODS:BALB/c mouse hearts were transplanted into C57BL/6, RelB-/- or LysMCrePirafl/fl mice, and a chronic rejection model was established by injecting CTLA-4-Ig. CD40-CD40L blockade in recipients by injecting anti-CD40L antibody. Allograft survival was monitored and histologically was assessed. Bone marrow-derived macrophages were treated with an anti-CD40 antibody. PIR-A expression was assessed via various methods in vivo and in vitro. Transcription factor expression levels were detected using RNA sequencing. DNA specifically bound to transcription factors was detected using ChIP-seq. RESULTS:CD40 and PIR-A were highly expressed and colocalized in macrophage-infiltrating allograft in the mouse model. CD40-CD40L blockade inhibited PIR-A expression and prolonged allograft survival. Conditional deletion of Pira in recipient's macrophages inhibited chronic rejection and promoted long-term allograft acceptance. Mechanistically, CD40 may activate transcription factor NF-κB2 translocation into the nucleus to up-regulate PIR-A expression, promoting chronic rejection of cardiac transplantation. NF-κB2 regulated PIR-A expression by binding to the intergenic region of Pira. CONCLUSIONS:Our data suggest that Pira is a potential target to induce long-term allograft tolerance. CD40 may activate transcription factor NF-κB2 translocation into the nucleus to up-regulate PIR-A expression, promoting chronic rejection of cardiac transplantation. The study findings provide novel therapeutic opportunities to promote transplant survival in clinical settings.

SET domain-containing lysine methyltransferase 7 (SETD7) is a critical enzyme that methylates lysine residues on both histone and non-histone proteins, thereby regulating gene expression and protein function. This methyltransferase plays a versatile and context-dependent role in a wide range of physiological processes, including cell differentiation, reactive oxygen species (ROS) signaling, oxidative stress regulation, and energy metabolism. SETD7's dual nature is highlighted by its paradoxical involvement in various diseases such as cancer, asthma, and Alzheimer's disease, where it can either promote or suppress pathological progression depending on the cellular environment and molecular context. The multifaceted functions of SETD7 underscore its importance in maintaining cellular homeostasis but also present significant challenges for therapeutic targeting. Although selective inhibitors like Cyproheptadine and (R)-PFI-2 have recently been identified, the development of highly specific and effective therapies remains complex due to SETD7's broad regulatory roles and the potential for unintended effects on normal physiological processes. These challenges necessitate nuanced therapeutic strategies, including the exploration of combination treatments and context-specific modulation to maximize efficacy while minimizing adverse outcomes. This review comprehensively explores SETD7's structure, subcellular localization, and diverse biological functions in both normal and disease states. By elucidating the dual and context-dependent nature of SETD7, it aims to provide a framework for future research focused on unraveling its molecular mechanisms and advancing targeted therapeutic approaches that leverage its unique regulatory capabilities.

ABSTRACT Objective Tumor‐induced osteomalacia with the culprit tumor located in the knee joint is rare in clinical practice, and previous literature has only been seen in case reports, which pose great challenges to the clinical diagnosis and treatment of such patients. The purpose is to elucidate clinical characteristics and orthopedic surgical treatment experience of tumor‐induced osteomalacia (TIO) with causative tumor located in the knee joint region. Methods Clinical data of all consecutive TIO patients with culprit tumors located in the knee joint region was retrospectively analyzed. All patients were surgically treated by an orthopedic bone and soft tissue tumor sub‐professional team at Peking Union Medical College Hospital from January 2015 to January 2025. The clinical distribution feature and surgical effects were analyzed, and clinical practice experience was presented. Results All nine patients were included in this study. All patients exhibited varying degrees of bone pain and 100% (9/9) of the patients had limited mobility, often accompanied by difficulties in sitting up, walking, and weakness or fatigue. Approximately 44.4% (4/9) of the patients had significantly shorter height after initial symptoms appeared. All patients underwent a total of 10 operations to control the causative tumors in the knee joint region. Culprit tumors were located in the patella (one case), infrapatellar fat pad (three cases), suprapatellar capsule (one case), popliteal fossa (three cases), and the entire knee joint (one case), respectively. There was only one case of skeletal involvement, one case with involvement of bones and soft tissues, and seven cases with soft tissue causative tumors. All the patients had a gradual increase in blood phosphorus levels in the short term after the first orthopedic surgery, after a follow‐up of 12 months to 10 years. During the follow‐up, no patients experienced recurrence. Conclusion The causative tumor for TIO in the knee joint region is hidden and has diverse locations; however, there is no established orthopedic surgical intervention strategy for these rare entities in clinical practice. Due to the unique anatomical location and complex structure of the knee joint, orthopedic surgeons can adopt different surgical approaches to completely remove the causative tumor. For these patients, the prognosis is satisfactory after complete tumor resection, and the condition can be effectively improved. These findings may help to improve the clinical diagnosis and treatment level of orthopedic physicians for this rare entity.

BACKGROUND:Due to its occult position, complex anatomical structure, and spatial relationships, the causative tumor of Tumor-Induced Osteomalacia (TIO) in the hip region is quite difficult to detect and qualitatively diagnose in clinical practice. In this regard, clinicians often lack sufficient knowledge about such tumors, leading to frequent missed diagnoses, misdiagnoses, and unreasonable treatment. OBJECTIVE:This study aimed to investigate the clinical characteristics of TIO patients with culprit soft tissue tumors in the hip region and evaluate the effect of surgical treatment on these individuals to improve clinicians' understanding of the rare phenomenon. METHODS:The clinical data of all patients, from January 2013 to January 2023, who underwent surgical treatment for hip located culprit soft tissue tumors by the subspecialty group on bone and soft tissue tumors at our institution, were retrospectively analysed. Specifically, the clinical characteristics and therapeutic effects were examined and the patients' clinical experience was summarized. RESULTS:Twenty-two patients, who met the inclusion criteria, were included. All patients experienced varying degrees of bone pain, commonly accompanied by weakness (16/22) and limited mobility (21/22), and 10 patients (45.5%) experienced a significant reduction in body height during the course of the disease. All patients underwent orthopedic surgery in the hip region, as hypophosphatemia occurred in all of them. Pathological diagnosis was confirmed to be consistent with causative tumors of TIO. All patients experienced a gradual increase in serum phosphorus postoperatively during short-term follow-up. The follow-up period was between 1 and 10 years, and the postoperative serum phosphorus levels were monitored at our hospital or other facilities close to the patients. CONCLUSIONS:Oncogenic soft tissue tumors for TIO in the hip region are occult, making clinical misdiagnoses or missed diagnoses highly likely. Therefore, enhancing the clinician's understanding of this rare condition is imperative. Notably, for TIO patient whose culprit tumor can be located, complete surgical resection of the causative tumor is the best treatment option. Furthermore, close postoperative monitoring of serum phosphorus is necessary, and patients should be subjected to long-term follow-up for prompt detection of recurrent conditions.

To date, organ transplantation remains an effective method for treating end-stage diseases of various organs.

Rationale : CD8 + T cells undergo a series of metabolic reprogramming processes during their activation and proliferation, including increased glycolysis, decreased aerobic oxidation of sugars, increased amino acid metabolism and increased protein synthesis. However, it is still unclear what factors regulate these metabolic reprogramming processes in CD8 + T cells in the tumor immune microenvironment. Methods : T cell chromobox protein 4 (CBX4) knock-out mice models were used to determine the role of CBX4 in CD8 + T cells on the tumor immune microenvironment and tumor progression. Flow cytometry, Cut-Tag qPCR, Chip-seq, immunoprecipitation, metabolite detection , lentivirus infection and adoptive T cells transfer were performed to explore the underlying mechanisms of CBX4 knock-out in promoting CD8+ T cell activation and inhibiting tumor growth. Results : We found that CBX4 expression was induced in tumor-infiltrating CD8 + T cells and inhibited CD8 + T cell function by regulating glucose metabolism in tumor tissue. Mechanistically, CBX4 increases the expression of the metabolism-associated molecule aldolase B (Aldob) through sumoylation of trans-acting transcription factor 1 (SP1) and Kr & uuml;ppel-like factor 3 (KLF3). In addition, Aldob inhibits glycolysis and ATP synthesis in T cells by reducing the phosphorylation of the serine/threonine protein kinase (Akt) and ultimately suppresses CD8 + T cell function. Significantly, knocking out CBX4 may improve the efficacy of anti-PD-1 therapy by enhancing the function of CD8 + T cells in the tumor microenvironment. Conclusion : CBX4 is involved in CD8 + T cell metabolic reprogramming and functional persistence in tumor tissues, and serves as an inhibitor in CD8 + T cells' glycolysis and effector function.