Parathyroid carcinoma (PC) is a rare but clinically aggressive endocrine malignancy with limited treatment options and a poorly defined tumor microenvironment (TME). To elucidate its cellular heterogeneity and spatial architecture, we integrated single-cell and spatial transcriptomic profiling with whole-exome sequencing and multiplex immunohistochemistry on eight parathyroid neoplasm specimens, including PC, parathyroid adenoma, and atypical parathyroid tumor. We identified a distinct progenitor-like endocrine subpopulation (Ca-1) enriched in CDC73-mutant PC, exhibiting stem-like properties, elevated cell cycle activity, and pronounced genomic instability. Spatial mapping revealed that Ca-1 cells preferentially localize at the leading edge, forming a fibroinflammatory niche characterized by the enrichment of inflammatory cancer-associated fibroblasts (iCAFs) and SPP1+ macrophages. Within this niche, the dipeptidyl peptidase 4 (DPP4) is selectively expressed in Ca-1 cells and iCAFs, implicating a potential paracrine axis driving stromal remodeling and immunosuppression. These findings suggest that a spatially organized ecosystem may promote PC progression through TME remodeling and highlight the DPP4-CXCL2 axis as a candidate pathway for future investigation in aggressive parathyroid neoplasms.

Parathyroid carcinoma (PC) is a rare endocrine malignancy with a poor prognosis. Preoperative diagnosis remains a major challenge in clinical practice because of limited diagnostic methods and non-specific clinical features. This study aimed to describe the distinct plasma metabolic profiles of PC and parathyroid adenoma (PA) patients and identify promising biomarkers for the preoperative differential diagnosis of PC. A total of 115 patients were enrolled in this retrospective study, including 70 patients (24 PC and 46 PA) in the discovery cohort and 45 patients (15 PC and 30 PA) in the validation cohort. Plasma samples were collected before operation. LC-MS/MS analysis was utilised on the discovery cohort to explore the metabolic profile and find out differentially abundant metabolites. Subsequently, potential diagnostic biomarkers were verified in an external validation cohort to find out novel biomarkers for the differential diagnosis of PC before surgery. Compared with the plasma samples of PA patients, a total of three upregulated and 42 downregulated metabolites were identified by MS/MS in the plasma samples of PC patients. The differentially abundant metabolites were significantly enriched in the arachidonic acid, tryptophan, and hormone metabolism pathways. Notably, 7-ketodeoxycholic acid (P = 0.002, AUC = 0.804) and tryptophan (P < 0.001, AUC = 0.838) were confirmed to show high accuracy in differential diagnosis in the validation cohort. Therefore, metabolomics analysis of parathyroid neoplasms revealed significant differences in metabolic profiles between PAs and PCs. The plasma levels of 7-ketodeoxycholic acid and tryptophan could serve as potential diagnostic biomarkers for PC.

In the ever-evolving arena of molecular biology, epigenetic modifications stand out as crucial determinants in the orchestration of cellular identity, function, and fate. This review analyzes the close relationship between epigenetics and tumor immunity, emphasizing the intricate interplay with the tumor microenvironment (TME). Rooted in the knowledge that the incidence of cancer correlates strongly with the biological and genetic age, we highlight DNA methylation as a cornerstone of the "epigenetic aging" process with close ties to tumorigenesis. The TME, with its diverse cellular and acellular constituents, is an active participant in tumor biology, further complicated by epigenetic alterations. These modifications, from DNA methylation to histone changes, not only shape the TME but are reciprocally influenced by it, reinforcing a cycle that propels malignancy. Through this exploration, we underline the importance of understanding this mutual relationship, as it holds significant implications for tumor growth, heterogeneity, and therapeutic resistance. Ultimately, this review illuminates the potential of harnessing epigenetic insights for innovative cancer therapeutic strategies, pointing towards a promising avenue for future cancer management.

Pancreatic cystic neoplasms (PCNs) carry variable malignant potential, requiring precise clinical management. However, the heterogeneity and progression of PCNs remain poorly understood. This study analyzed the microbiome, metabolome, and ionome profiles of cyst fluids from 188 patients, including 165 with PCNs and 23 with other cyst types, using PacBio full-length 16S/ITS sequencing, LC-MS/MS, and ICP-MS. Bioinformatic analyses were performed, and metabolic enzyme and endoplasmic reticulum (ER) stress-related gene expression were examined using the PAAD TCGA dataset. PCNs were classified into distinct histopathological subtypes, including mucinous cystic lesions (MCLs) and serous cystic lesions (SCLs). MCLs demonstrated lower microbial diversity compared to SCLs, indicating microbial instability. Streptococcus and Staphylococcus were identified as key taxa in intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs), respectively. MCLs exhibited metabolic shifts towards lipid metabolism, while IPMNs showed distinct metabolic profiles potentially reflecting inflammation-related metabolic reprogramming. Ionic diversity varied among subtypes, with MCLs showing reduced diversity and IPMNs presenting broader ionic profiles. Palmitic acid (PA), a metabolite linked to Streptococcus, may contribute to pro-inflammatory metabolic alterations in IPMN. Our preliminary experiments demonstrated that co-culturing Streptococcus orails (S. orails) with ASAN-PaCa cells promoted their proliferation, accompanied by an elevation of PA levels in the supernatant. This integrative microbiome-metabolome-ionome analysis highlights histopathological heterogeneity among PCNs. While mechanistic associations remain to be fully defined, mucinous lesions may be more susceptible to microbe-driven metabolic disruption, with Streptococcus-associated lipid alterations as a potential contributing factor.

Parathyroid carcinoma (PC) is a rare endocrine malignancy with a poor prognosis. The preoperative diagnosis of PC is difficult because of the lack of specific clinical features and effective diagnostic methods. Proteomics research can provide new strategies for preoperative diagnosis, but the proteomic profile of plasma from PC patients is still unavailable. Plasma samples from 10 PC patients and 10 PA patients were collected before surgery, and quantitative label-free proteomics analysis was applied to explore the proteomic landscape of parathyroid neoplasms. Next, parallel reaction monitoring (PRM) analysis was used to verify the possible biomarkers in plasma from 24 PC patients and 46 PA patients. Finally, the expression of potential biomarkers in parathyroid tumor tissues was validated. Compared with those in PA patients, 76 overexpressed proteins and 62 underexpressed proteins were identified in the plasma of PC patients. These differentially expressed proteins were closely associated with the immune system according to functional enrichment analysis. PRM analysis revealed that four proteins, including myoglobin (p = 0.048), polymeric immunoglobulin receptor (pIgR) (p = 0.021), coronin-1 A (p = 0.024), and immunoglobulin heavy variables 2–26 (p = 0.029), were promising diagnostic biomarkers for PCs. Coronin-1 A (p = 0.038) and glucose-6-phosphate isomerase (p = 0.041) were significantly related to overall survival (OS) of PC patients. Moreover, coronin-1 A was confirmed to be significantly overexpressed in parathyroid carcinoma tissues. The proteomic profile of plasma from patients with PCs significantly differed from that of plasma from patients with PAs. Myolobin, pIgR, coronin-1 A and immunoglobulin heavy variable 2–26 in plasma may be potential biomarkers for the preoperative diagnosis of PCs. Coronin-1 A may serve as a novel biomarker for the differential diagnosis of parathyroid carcinoma in not only preoperative but also postoperative diagnosis.

Pancreatic cystic neoplasms (PCNs) are a heterogeneous group of pancreatic lesions with the potential for malignant transformation. Next-generation sequencing has revealed subtype-specific driver mutations and pathways that govern the initiation and progression of PCN. Evidence suggests that subtype-specific genetic trajectories and temporal sequences of genetic and molecular events are pivotal in determining disease progression and malignant transformation. Novel methodologies in genetic testing, particularly through minimally invasive cyst fluid analysis and advanced tissue-based sequencing, have profoundly enhanced diagnostic accuracy and the molecular classification of PCNs. Furthermore, these genetic insights guide risk stratification, clinical decision-making, and personalized therapeutic interventions. This review systematically summarizes current genomic insights into the molecular landscape of PCNs, critically evaluates the comparative diagnostic performance of cyst fluid versus tissue-based genetic testing, and integrates these findings into a practical framework for clinical management.

BACKGROUND:Membrane (m) CD58 is a co-stimulatory ligand that binds to CD2, and the CD2-(m) CD58 axis participates in lymphocyte activation. In addition to mCD58, a soluble form of CD58 (sCD58) has been reported in human serum, urine, and in vitro cell culture supernatants. The role of sCD58 in the tumor immune microenvironment of pancreatic ductal adenocarcinoma (PDAC) is currently unknown. METHODS:The expression and prognostic role of CD58 in PDAC tissues were analyzed using various public databases. Then, the phenomenon of expressional separation of CD58 in PDAC cells induced by macrophages was observed by flow cytometry and ELISA, where the decrease of mCD58 on the membrane surface is accompanied by the increase of sCD58 in the supernatant. The molecular mechanisms of the expressional separation of CD58 were further explored by focusing on the TGF-β signaling pathway. The effects of expressional separation of CD58 on the immune activity and killing ability of T/NK cells for PDAC were determined in co-culture models. Furthermore, subcutaneous tumor-bearing models, lung metastasis models, and intraperitoneal dissemination models were used to confirm the in vitro data. Finally, the diagnostic and prognostic roles of serum sCD58 were determined by using 561 samples from PDAC patients, benign pancreatic disease patients, and healthy controls. RESULTS:Elevated CD58 expression in PDAC tissues was associated with worse clinical outcomes. After co-culture with PDAC cells, macrophages adopted an M2 phenotype, characterized by a high expression level of TGF-β. Co-cultured macrophages could induce the expressional separation of CD58 in PDAC cells. Activation of the TGF-β/Smad2/3 pathway markedly promoted this separation, and pathway inhibition largely blocked it. In vitro and in vivo assays revealed that mCD58 engaged CD2 on T/NK cells, facilitated their activation, enhanced their cytotoxicity, and stimulated the release of the anti-tumoral cytokines IFN-γ and TNF-α. Conversely, local high concentrations of sCD58 accumulation in PDAC tissues interfered with the CD2-CD58 axis by competitively binding CD2, inhibited the activation of T/NK cells, reduced T/NK cytotoxicity, and the secretion of IFN-γ and TNF-α. Furthermore, serum sCD58 levels were higher in the PDAC patients than in the healthy controls or patients with benign pancreatic diseases. sCD58 improved the diagnostic and prognostic power of CA199 in PDAC patients. A combined model incorporating CA199, TGF-β1, and sCD58 yielded an AUC (area under the curve) value of 0.946 for overall diagnosis. In the CA199 negative cohort, the combined model of TGF-β and sCD58 achieved an AUC of 0.955. CONCLUSIONS:This study uncovers a novel vicious crosstalk among macrophages, T/NK cells, and PDAC cells within the tumor microenvironment. Macrophages drive the expressional separation of CD58 via the TGF-β/Smad2/3 signaling pathway. This shift suppresses T/NK-cell activity, allows tumor cells to evade immune killing, and accelerates PDAC progression. In addition, serum sCD58 emerges as a promising diagnostic and prognostic biomarker for PDAC.

Ferroptosis, a novel form of cell death triggered by iron-dependent phospholipid peroxidation, presents significant therapeutic potential across diverse cancer types. Central to cellular metabolism, the metabolic pathways associated with ferroptosis are discernible in both cancerous and immune cells. This review begins by delving into the intricate reciprocal regulation of ferroptosis between cancer and immune cells. It subsequently details how factors within the tumor microenvironment (TME) such as nutrient scarcity, hypoxia, and cellular density modulate ferroptosis sensitivity. We conclude by offering a comprehensive examination of distinct immunophenotypes and environmental and metabolic targets geared towards enhancing ferroptosis responsiveness within the TME. In sum, tailoring precise ferroptosis interventions and combination strategies to suit the unique TME of specific cancers may herald improved patient outcomes.

Previous studies have reported the correlation between gut microbiota (GM), GM-derived metabolites, and various intestinal and extra-intestinal cancers. However, limited studies have investigated the correlation between GM, GM-derived metabolites, and osteosarcoma (OS). This study successfully established a female BALB/c nude mouse model of OS. Mice (n = 14) were divided into the following two groups (n = 7/group): OS group named OG, injected with Saos-2 OS cells; normal control group named NCG, injected with Matrigel. The GM composition and metabolites were characterized using 16S rDNA sequencing and untargeted metabolomics, respectively. Bioinformatics analysis revealed that amino acid metabolism was dysregulated in OS. The abundances of bone metabolism-related genera Alloprevotella, Rikenellaceae_RC9_gut_group, and Muribaculum were correlated with amino acid metabolism, especially histidine metabolism. These findings suggest the correlation between GM, GM-derived metabolites, and OS pathogenesis. Clinical significance: The currently used standard therapeutic strategies for OS, including surgery, chemotherapy, and radiation, are not efficacious. The findings of this study provided novel insights for developing therapeutic, diagnostic, and prognostic strategies for OS.

Single-cell RNA sequencing (scRNA-seq) is an emerging technology used for cellular transcriptome analysis. The application of scRNA-seq has led to profoundly advanced oncology research, continuously optimizing novel therapeutic strategies. Intratumor heterogeneity extensively consists of all tumor components, contributing to different tumor behaviors and treatment responses. Tumor-associated macrophages (TAMs), the core immune cells linking innate and adaptive immunity, play significant roles in tumor progression and resistance to therapies. Moreover, dynamic changes occur in TAM phenotypes and functions subject to the regulation of the tumor microenvironment. The heterogeneity of TAMs corresponding to the state of the tumor microenvironment has been comprehensively recognized using scRNA-seq. Herein, we reviewed recent research and summarized variations in TAM phenotypes and functions from a developmental perspective to better understand the significance of TAMs in the tumor microenvironment.

Patients with peritoneal metastatic pancreatic ductal adenocarcinoma (pmPDAC) with high-level serum carbohydrate antigens (CAs) always suffer extremely dismal prognosis, with a median survival of several months. Herein, we reported a case of pmPDAC with high serum CAs who had long-term clinical remission with normalization of CAs after chemoradiation. In November 2019, a 64-year-old male patient was admitted to our center with a solid mass measuring 2.8 × 2.5 × 2.0 cm in the body of the pancreas near the celiac trunk. Positron emission tomography-computed tomography (PET-CT) revealed an standardized uptake value max (SUVmax) of 4.2. The serum CA 242 level exceeded 150.0 U/mL (normal range: 0–20 U/mL), and CA 19-9 was elevated at 975.2 U/mL (normal range: 0–34 U/mL). During laparotomy, the tumor was found to encircle the celiac trunk over 180°, with several small peritoneal nodules in the lesser omental cavity. Pathological examination confirmed the diagnosis of pmPDAC. Next-generation sequencing revealed RAS G12V, EGFR mutation (-), low tumor mutation burden (TMB), and microsatellite stability (MSS). The patient underwent 6 cycles of the AG regimen (gemcitabine plus nab-paclitaxel), resulting in significant tumor shrinkage and a sharp decline in CAs. Partial remission was achieved. However, due to intolerant neurotoxicity, the AG regimen was discontinued. Subsequently, synchronous oral fluorouracil (S1) and radiation therapy were administered. Five months after radiation treatment, all CAs normalized. Oral S1 was continued for an additional 3 months. Eventually, all anti-cancer drugs were stopped. Computed tomography scans indicated that the tumor still surrounded the celiac trunk and common hepatic artery. After a thorough discussion, a wait-and-see strategy was adopted. Remarkably, 32 months after stopping anti-cancer medication, the patient remains in good health, with sustained normalization of CAs. At the last follow-up, he had lived for 50 months, and the normalization of the CAs was sustained for 36 months. Although he still suffers the risk of disease progression, it is a successful case of state-of-the-art chemoradiation for a dismal pmPDAC patient.

Pancreatic cancer is distinguished by an immunosuppressive tumor microenvironment (TME) that facilitates cancer progression. The assembly of the TME involves numerous contributing factors. Migrasomes, recently identified as cellular organelles in migrating cells, play a pivotal role in intercellular signaling. However, research into their involvement in cancers remains nascent. Thus far, whether pancreatic cancer cells generate migrasomes and their potential role in TME formation remains unexplored. In this study, it was found that both murine and human pancreatic cancer cells could indeed generate migrasomes, termed pancreatic cancer cell-derived migrasomes (PCDMs), which actively promote cancer progression. Moreover, utilizing chemokine antibody arrays and quantitative mass spectrometry analysis, we observed significant differences between the chemokines, cytokines, and proteins present in PCDMs compared to their originating cell bodies. Notably, PCDMs exhibited an enrichment of immunosuppression-inducing factors. Furthermore, macrophages could directly uptake PCDMs, leading to the expression of high levels of M2-like markers and secretion of tumor-promoting factors. PCDM-induced macrophages played a pivotal role in inhibiting T cell proliferation and activation partially through ARG-1. In summary, this study provides compelling evidence that pancreatic cancer cells generate migrasomes, which play a crucial role in promoting tumor progression by contributing to an immunosuppressive TME. The exploration of migrasomes as a therapeutic target could pave the way for the development of tailored immunotherapies for pancreatic cancer.

PurposeParathyroid carcinoma (PC) is a rare malignancy with a poor prognosis. Diagnosis of PC is often difficult in clinical practice and efficient diagnostic markers are still needed for differential diagnosis. Aberrant glycosylations of glycoproteins were identified with lectin microarray in various cancers, while relevant information is lacking in PC. MethodsIn this study, 8 PC and 6 parathyroid adenoma (PA) tissues were assessed using a microarray consisting of 70 lectins. Overall lectin-specific glycosylation patterns were compared between PA and PC tissues. Lectins with significant differential response between PC and PA were further validated by lectin histochemistry. ResultsThe difference in signal intensities was found in 71.4% (50/70) of the lectins between the two groups (P < 0.05). The vast majority of PCs had higher intensity signals than PAs (PCs vs. PAs, ratio >1) and amaranthus caudatus (ACL) showed the most significantly different response between them (ratio = 2.45). Lectin histochemistry further confirmed higher ACL intensity in PCs than in PAs. The differentially expressed glycans in PC tissues were primarily glucose, mannose, and galactose-based. ConclusionPC presented unique glycomic features and ACL may serve as a candidate diagnostic marker for PC.

The immune system provides full protection for the body by specifically identifying 'self' and removing 'others'; thus protecting the body from diseases. The immune system includes innate immunity and adaptive immunity, which jointly coordinate the antitumor immune response. T cells, natural killer (NK) cells and tumor-associated macrophages (TAMs) are the main tumor-killing immune cells active in three antitumor immune cycle. Cancer immunotherapy focusses on activating and strengthening immune response or eliminating suppression from tumor cells in each step of the cancer-immunity cycle; thus, it strengthens the body's immunity against tumors. In this review, the antitumor immune cycles of T cells, natural killer (NK) cells and tumor-associated macrophages (TAMs) are discussed. Co-stimulatory and co-inhibitory molecules in the three activity cycles and the development of drugs and delivery systems targeting these molecules are emphasized, and the current state of the art of drug delivery systems for cancer immunotherapy are summarized.

In recent decades, immune checkpoint blockade and chimeric antigen receptor T cell (CAR-T) therapy are two milestone achievements in clinical immunotherapy. However, both show limited efficacies in most solid neoplasms, which necessitates the exploration of new immunotherapeutic modalities. The failure of CAR-T and immune checkpoint blockade in several solid neoplasms is attributed to multiple factors, including low antigenicity of tumor cells, low infiltration of effector T cells, and diverse mechanisms of immunosuppression in the tumor microenvironment. New adoptive cell therapies have been attempted for solid neoplasms, including TCR-T, CAR-natural killer cells (CAR-NK), and CAR-macrophages (CAR-M). Compared to CAR-T, these new adoptive cell therapies have certain advantages in treating solid neoplasms. In this review, we summarized the 40-year evolution of adoptive cell therapies, then focused on the advances of TCR-T, CAR-NK, and CAR-M in solid neoplasms and discussed their potential clinical applications.

Tumour microenvironment has been recognized as a crucial factor influencing disease progression. However, relevant features and functions are insufficiently understood in parathyroid neoplasia. Single-cell RNA sequencing was performed to profile the transcriptome of 27,251 cells from 4 parathyroid adenoma (PA) tissue samples. External transcriptomic datasets and immunofluorescence staining of a tissue microarray were set for expression validation. Eight major cell types and various subpopulations were finely identified in PA. We found that a subcluster of tumour endocrine cells with low copy number variation probably presented as a resting state. Diverse infiltrating immune cell subtypes were identified, constructing an immunosuppressive microenvironment. Tumour-associated macrophages, which indicated an anti-inflammatory phenotype, were significantly increased in PA. Inflammatory tumour-associated fibroblasts (iTAFs) were newly verified and highlighted on the role of stromal-immune crosstalk. Positive correlation between iTAFs and increased CD163(+) macrophages was uncovered. Moreover, CXCL12 receptor signalling is important for tumour angiogenesis and immune infiltration. Our findings provide a comprehensive landscape interpreting tumour cell heterogeneity, cell diversity, and immune regulation in parathyroid neoplasia. The valuable resources may promote the understanding of parathyroid tumour microenvironment.