Cancer immunometabolism: advent, challenges, and perspective.

For decades, great strides have been made in the field of immunometabolism. A plethora of evidence ranging from basic mechanisms to clinical transformation has gradually embarked on immunometabolism to the center stage of innate and adaptive immunomodulation. Given this, we focus on changes in immunometabolism, a converging series of biochemical events that alters immune cell function, propose the immune roles played by diversified metabolic derivatives and enzymes, emphasize the key metabolism-related checkpoints in distinct immune cell types, and discuss the ongoing and upcoming realities of clinical treatment. It is expected that future research will reduce the current limitations of immunotherapy and provide a positive hand in immune responses to exert a broader therapeutic role.

The stromal microenvironment endows pancreatic neuroendocrine tumors with spatially specific invasive and metastatic phenotypes.

Cancer-associated fibroblasts (CAFs) play an important role in a variety of cancers. However, the role of tumor stroma in nonfunctional pancreatic neuroendocrine tumors (NF-PanNETs) is often neglected. Profiling the heterogeneity of CAFs can reveal the causes of malignant phenotypes in NF-PanNETs. Here, we found that patients with high stromal proportion had poor prognosis, especially for that with infiltrating stroma (stroma and tumor cells that presented an infiltrative growth pattern and no regular boundary). In addition, myofibroblastic CAFs (myCAFs), characterized by FAP+ and α-SMAhigh, were spatially closer to tumor cells and promoted the EMT and tumor growth. Intriguingly, only tumor cells which were spatially closer to myCAFs underwent EMT. We further elucidated that myCAFs stimulate TGF-ß expression in nearby tumor cells. Then, TGF-ß promoted the EMT in adjacent tumor cells and promoted the expression of myCAFs marker genes in tumor cells, resulting in distant metastasis. Our results indicate that myCAFs cause spatial heterogeneity of EMT, which accounts for liver metastasis of NF-PanNETs. The findings of this study might provide possible targets for the prevention of liver metastasis.

Brain connectomics improve prediction of 1-year decreased quality of life in breast cancer: A multi-voxel pattern analysis.

PURPOSE: Whether brain connectomics can predict 1-year decreased Quality of Life (QoL) in patients with breast cancer are unclear. A longitudinal study was utilized to explore their prediction abilities with a multi-center sample. METHODS: 232 breast cancer patients were consecutively enrolled and 214 completed the 1-year QoL assessment (92.2%). Resting state functional magnetic resonance imaging was collected before the treatment and a multivoxel pattern analysis (MVPA) was performed to differentiate whole-brain resting-state connectivity patterns. Net Reclassification Improvement (NRI) as well as Integrated Discrimination Improvement (IDI) were calculated to estimate the incremental value of brain connectomics over conventional risk factors. RESULTS: Paracingulate Gyrus, Superior Frontal Gyrus and Frontal Pole were three significant brain areas. Brain connectomics yielded 7.8-17.2% of AUC improvement in predicting 1-year decreased QoL. The NRI and IDI ranged from 20.27 to 54.05%, 13.21-33.34% respectively. CONCLUSION: Brain connectomics contribute to a more accurate prediction of 1-year decreased QoL in breast cancer. Significant brain areas in the prefrontal lobe could be used as potential intervention targets (i.e., Cognitive Behavioral Group Therapy) to improve long-term QoL outcomes in breast cancer.

SMAD4 endows TGF-ß1-induced highly invasive tumor cells with ferroptosis vulnerability in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive malignancy prone to recurrence and metastasis. Studies show that tumor cells with increased invasive and metastatic potential are more likely to undergo ferroptosis. SMAD4 is a critical molecule in the transforming growth factor ß (TGF-ß) pathway, which affects the TGF-ß-induced epithelial-mesenchymal transition (EMT) status. SMAD4 loss is observed in more than half of patients with PDAC. In this study, we investigated whether SMAD4-positive PDAC cells were prone to ferroptosis because of their high invasiveness. We showed that SMAD4 status almost determined the orientation of transforming growth factor ß1 (TGF-ß1)-induced EMT via the SMAD4-dependent canonical pathway in PDAC, which altered ferroptosis vulnerability. We identified glutathione peroxidase 4 (GPX4), which inhibited ferroptosis, as a SMAD4 down-regulated gene by RNA sequencing. We found that SMAD4 bound to the promoter of GPX4 and decreased GPX4 transcription in PDAC. Furthermore, TGF-ß1-induced high invasiveness enhanced sensitivity of SMAD4-positive organoids and pancreas xenograft models to the ferroptosis inducer RAS-selective lethal 3 (RSL3). Moreover, SMAD4 enhanced the cytotoxic effect of gemcitabine combined with RSL3 in highly invasive PDAC cells. This study provides new ideas for the treatment of PDAC, especially SMAD4-positive PDAC.

NMI promotes tumor progression and gemcitabine resistance in pancreatic cancer via STAT3-IFIT3 axis.

N-myc and STAT interactor (NMI) has been reported to interact with several transcription factors, including STATs family, c-Myc, N-Myc, and BRCA1, to indirectly affect transcription events and participate in multiple cellular processes. However, its function in pancreatic ductal adenocarcinoma (PDAC) has seldom been studied. In this study, we investigated the regulation of NMI on PDAC progression and uncovered the underlying molecular mechanisms. We found that NMI expression was significantly upregulated in PDAC and high NMI expression was related to a worse patient survival. Cell proliferation and migration assay, including cell viability, transwell assay, wound healing, and subcutaneous mouse model were utilized to confirm the function of NMI in PDAC progression. Downregulation of NMI abrogates tumor progression of PDAC both in vitro and in vivo. RNA sequencing was utilized to identify the downstream molecules of NMI and interferon-induced protein with tetratricopeptide repeats 3 (IFIT3) was confirmed to be regulated by NMI in both mRNA and protein level. The binding function of NMI to STAT3 was essential in regulating the IFIT3 expression. Moreover, the NMI/STAT3-IFIT3 axis was identified to markedly facilitate the gemcitabine resistance in PDAC cells.

Heterogeneity in resilience patterns and its prediction of 1-year quality of life outcomes among patients with newly diagnosed cancer: An exploratory piecewise growth mixture model analysis.

PURPOSE: This study was designed to explore the impact of a new cancer diagnosis on resilience of patients and whether the resilience patterns could predict Quality of Life (QoL) in the first year. METHODS: An exploratory linear piecewise growth mixture modeling (PGMM) with one hypothetical dot (3 months since diagnosis, T1) was employed to identify different resilience patterns and growth in 289 patients with different cancer diagnoses at five assessment occasions (T0-T4). Logistic regression analysis was performed to select potential predictors and receiver operating characteristic (ROC) curve analysis was utilized to test PGMM's discriminative ability against 1-year QoL. RESULTS: Five discrete resilience trajectories with two growing trends were identified, including "Transcendence" (7.3%), "Resilient" (47.4%), "Recovery" (18.7%), "Damaged" (14.9%) and "Maladaption" (11.8%). Advanced stage, colorectal cancer, and receiving surgery therapy were significant predictors of negative resilience trajectories ("Damaged" or "Maladaption"). Discriminative ability was good for PGMM (AUC = 0.81, 95%CI, 0.76-0.85, P < 0.0001). CONCLUSION: Heterogeneity is identified in resilience growth before and after 3 months since diagnosis. 26.7% newly diagnosed patients need additional attention especially for those with advanced colorectal cancer and receiving surgery therapy.

Lactate-induced protein lactylation: A bridge between epigenetics and metabolic reprogramming in cancer.

Lactate is not only an endpoint of glycolysis but is gradually being discovered to play the role of a universal metabolic fuel for energy via the 'lactate shuttle' moving between cells and transmitting signals. The glycolytic-dependent metabolism found in tumours and fast-growing cells has made lactate a pivotal player in energy metabolism reprogramming, which enables cells to obtain abundant energy in a short time. Moreover, lactate can provide favourable conditions for tumorigenesis by shaping the acidic tumour microenvironment, recruiting immune cells, etc. and the recently discovered lactate-induced lactylation moves even further on pro-tumorigenesis mechanisms of lactate production, circulation and utilization. As with other epigenetic modifications, lactylation can modify histone proteins to alter the spatial configuration of chromatin, affect DNA accessibility and regulate the expression of corresponding genes. What's more, the degree of lactylation is inseparable from the spatialized lactate concentration, which builds a bridge between epigenetics and metabolic reprogramming. Here, we review the important role of lactate in energy reprogramming, summarize the latest finding of lactylation in tumorigenesis and try to explore therapeutic strategies in oncotherapy that can kill two birds with one stone.

A new glance at autophagolysosomal-dependent or -independent function of transcriptional factor EB in human cancer.

Autophagy-lysosome system plays a variety of roles in human cancers. In addition to being implicated in metabolism, it is also involved in tumor immunity, remodeling the tumor microenvironment, vascular proliferation, and promoting tumor progression and metastasis. Transcriptional factor EB (TFEB) is a major regulator of the autophagy-lysosomal system. With the in-depth studies on TFEB, researchers have found that it promotes various cancer phenotypes by regulating the autophagolysosomal system, and even in an autophagy-independent way. In this review, we summarize the recent findings about TFEB in various types of cancer (melanoma, pancreatic ductal adenocarcinoma, renal cell carcinoma, colorectal cancer, breast cancer, prostate cancer, ovarian cancer and lung cancer), and shed some light on the mechanisms by which it may serve as a potential target for cancer treatment.

Measuring resilience by cognitive diagnosis models and its prediction of 6-month quality of life in Be Resilient to Breast Cancer (BRBC).

Objective: The application of advanced Cognitive Diagnosis Models (CDMs) in the Patient Reported Outcome (PRO) is limited due to its complex statistics. This study was designed to measure resilience using CDMs and its prediction of 6-month Quality of Life (QoL) in breast cancer. Methods: A total of 492 patients were longitudinally enrolled from Be Resilient to Breast Cancer (BRBC) and administered with 10-item Resilience Scale Specific to Cancer (RS-SC-10) and Functional Assessment of Cancer Therapy-Breast (FACT-B). Generalized Deterministic Input, Noisy "And" Gate (G-DINA) was performed to measure cognitive diagnostic probabilities (CDPs) of resilience. Integrated Discrimination Improvement (IDI) and Net Reclassification Improvement (NRI) were utilized to estimate the incremental prediction value of cognitive diagnostic probabilities over total score. Results: CDPs of resilience improved prediction of 6-month QoL above conventional total score. AUC increased from 82.6-88.8% to 95.2-96.5% in four cohorts (all P < 0.001). The NRI ranged from 15.13 to 54.01% and IDI ranged from 24.69 to 47.55% (all P < 0.001). Conclusion: CDPs of resilience contribute to a more accurate prediction of 6-month QoL above conventional total score. CDMs could help optimize Patient Reported Outcomes (PROs) measurement in breast cancer.

MEN1 Degradation Induced by Neddylation and the CUL4B-DCAF7 Axis Promotes Pancreatic Neuroendocrine Tumor Progression.

Pancreatic neuroendocrine tumors (PanNET) are a group of rare sporadic malignant tumors in the pancreas. MEN1 is the most frequently mutated gene in PanNETs. The MEN1-encoded protein is a typical tumor suppressor that forms a complex with epigenetic and transcription factors and is an attractive target for therapeutic interventions for patients with PanNET. A better understanding of the regulation of MEN1 protein expression in PanNETs could identify strategies for targeting MEN1. Here, we found that the neddylation pathway and DCAF7-mediated ubiquitination regulated MEN1 protein expression. Increased expression of members of the neddylation pathway and DCAF7 was found in PanNET tissues compared with paired-adjacent tissues and was associated with poor prognosis in patients with PanNET. Suppression of neddylation using the neddylation inhibitor MLN4924 or RNA interference significantly induced MEN1 accumulation and repressed cancer-related malignant phenotypes. CUL4B and DCAF7 promoted MEN1 degradation by binding and catalyzing its ubiquitination. In PanNET cells resistant to everolimus, a pharmacologic mTOR inhibitor widely used for advanced PanNET patient treatment, the downregulation of DCAF7 expression overcame resistance and synergized with everolimus to suppress mTOR activation and to inhibit cancer cell growth. The effects of DCAF7 loss could be counteracted by the simultaneous knockdown of MEN1 both in vitro and in vivo. The inverse correlation between DCAF7 and MEN1 was further validated in clinical specimens. This study revealed that the posttranslational control of MEN1 expression in PanNET is mediated by neddylation and the CUL4B-DCAF7 axis and identifies potential therapeutic targets in patients with MEN1-associated PanNET. SIGNIFICANCE: Identification of neddylation and ubiquitination pathways that regulate MEN1 protein stability provides an opportunity for therapeutic interventions for treating patients with pancreatic neuroendocrine tumors.

Proteomic and metabolomic approaches elucidate the molecular mechanism of emodin against neuropathic pain through modulating the gamma-aminobutyric acid (GABA)-ergic pathway and PI3K/AKT/NF-κB pathway.

Neuropathic pain (NeP) is a major health concern. Due to the complex pathological mechanisms, management of NeP is challenging. Emodin, a natural anthraquinone derivative, exerts excellent analgesic effects. However, its mechanisms of action are still poorly understood. In this study, we investigated the mechanisms underlying pain-relief effects of emodin in the cerebral cortex using proteomic and metabolomic approaches. After 15 days of emodin administration, the mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) values in the emodin groups were significantly higher than those in the chronic constriction injury (CCI) group (p < .05), suggesting emodin treatment could reverse CCI-induced hyperalgesia. Emodin treatment evoked the expression alteration of 402 proteins (153 up-regulated and 249 down-regulated) in the CCI models, which were primarily involved in PI3K/AKT signaling pathway, gamma-aminobutyric acid (GABA) receptor signaling, complement and coagulation cascades, cGMP/PKG signaling pathway, MAPK signaling pathway, and calcium signaling pathway. In parallel, emodin intervention regulated the abundance alteration of 27 brain metabolites (20 up-regulated and 7 down-regulated) in the CCI rats, which were primarily implicated in carbon metabolism, biosynthesis of amino acids, pentose phosphate pathway, and glucagon signaling pathway. After a comprehensive analysis and western blot validation, we demonstrated that emodin alleviated NeP mainly through regulating GABAergic pathway and PI3K/AKT/NF-κB pathway.

Recent progress of experimental model in pancreatic neuroendocrine tumors: drawbacks and challenges.

The neuroendocrine neoplasm, in general, refers to a heterogeneous group of all tumors originating from peptidergic neurons and neuroendocrine cells. Neuroendocrine neoplasms are divided into two histopathological subtypes: well-differentiated neuroendocrine tumors and poorly differentiated neuroendocrine carcinomas. Pancreatic neuroendocrine tumors account for more than 80% of pancreatic neuroendocrine neoplasms. Due to the greater proportion of pancreatic neuroendocrine tumors compared to pancreatic neuroendocrine carcinoma, this review will only focus on them. The worldwide incidence of pancreatic neuroendocrine tumors is rising year by year due to sensitive detection with an emphasis on medical examinations and the improvement of testing technology. Although the biological behavior of pancreatic neuroendocrine tumors tends to be inert, distant metastasis is common, often occurring very early. Because of the paucity of basic research on pancreatic neuroendocrine tumors, the mechanism of tumor development, metastasis, and recurrence are still unclear. In this context, the representative preclinical models simulating the tumor development process are becoming ever more widely appreciated to address the clinical problems of pancreatic neuroendocrine tumors. So far, there is no comprehensive report on the experimental model of pancreatic neuroendocrine tumors. This article systematically summarizes the characteristics of preclinical models, such as patient-derived cell lines, patient-derived xenografts, genetically engineered mouse models, and patient-derived organoids, and their advantages and disadvantages, to provide a reference for further studies of neuroendocrine tumors. We also highlight the method of establishment of liver metastasis mouse models.

Systems biology strategy and experimental validation to uncover the pharmacological mechanism of Xihuang Pill in treating non-small cell lung cancer.

BACKGROUND: Non-small cell lung cancer (NSCLC) accounts for almost 85% of lung cancer-related deaths worldwide. Xihuang Pill (XHP) is a representative anticancer Chinese patented medicine used to treat NSCLC in China. However, to date, a systematic analysis of XHP's antitumour effects and its impact on the immune microenvironment has not been performed. PURPOSE: Based on the systems biology strategy and experimental validation, the present study aimed to investigate the pharmacological mechanisms involved in treating NSCLC with XHP. METHODS: A subcutaneous tumour model was established to evaluate XHP's tumour-inhibitory effect in BALB/c nude mice. RNA sequencing (RNA-seq) and bioinformatics analysis were conducted to identify differentially expressed genes (DEGs) and signalling pathways related to XHP treatment. Network analysis based on network pharmacology and protein-to-protein networks was applied to identify the compounds and genes targeted by XHP. External data from the TCGA-NSCLC cohort were used to verify the clinical significance of XHP-targeted genes in NSCLC. The expression of survival-related candidate genes after XHP treatment was verified via qPCR. The protein expression of calcium voltage-gated channel subunit alpha 1C (CACNA1C) in different NSCLC cell lines was analysed in the Human Protein Atlas database (HPA) and DepMap Portal. Using the Estimation of STromal and Immune cells in MAlignant Tumour tissues using Expression data (ESTIMATE) algorithm and the single-sample gene set enrichment analysis (ssGSEA) algorithm uncovered the role of CACNA1C in the NSCLC tumour microenvironment (TME). RESULTS: XHP (2 g/kg/d) significantly inhibited the growth of transplanted A549 tumours. RNA-seq identified a total of 529 DEGs (189 upregulated and 340 downregulated). In addition, 542 GO terms, 41 significant KEGG pathways, 9 upregulated hallmarks pathways, and 18 downregulated hallmark pathways were enriched. These GO terms and signalling pathways were closely related to cell proliferation, immunity, energy metabolism, and the inflammatory response of NSCLC. In addition, XHP's network pharmacology analysis identified 301 compounds and 1,432 target genes. A comprehensive strategic analysis identified CACNA1C as a promising gene by which XHP targets and regulates the TME of NSCLC, benefiting patient survival. CACNA1C expression was positively correlated with both the immune score and stromal score but negatively correlated with the tumour purity score. Additionally, CACNA1C expression was significantly correlated with the infiltration levels of 15 types of immune cells and the expression levels of 6 well-known checkpoint genes. CONCLUSIONS: Our results show that by regulating the pathways associated with cell proliferation and immunity, XHP can suppress cancer cell growth in NSCLC. Additionally, XHP may increase the expression of CACNA1C to suppress immune cell infiltration and regulate the expression of checkpoint-related genes, thereby improving the overall survival of NSCLC patients.

Hernandezine induces autophagic cell death in human pancreatic cancer cells via activation of the ROS/AMPK signaling pathway.

Hernandezine (Her) is a bisbenzylisoquinoline alkaloid extracted from the traditional Chinese herbal medicine Thalictrum glandulosissimum. Evidence shows that Her is a natural agonist of adenosine monophosphate (AMP)-activated protein kinase (AMPK) and induces apoptosis and autophagy in tumor cells. In this study, we investigated the role of autophagy in Her-induced cell death in human pancreatic cancer cell lines. We showed that Her dose-dependently suppressed cell proliferation, promoted autophagy and induced autophagic death in pancreatic ductal adenocarcinoma (PDAC) cell lines Capan-1 and SW1990. The IC50 values of Her in inhibition of Capan-1 and SW1990 cells were 47.7 µM and 40.1 µM, respectively. Immunoblotting showed that Her (1-40 µM) promoted the conversion of LC3-I to LC3-II, and Her exerted concentration-dependent and time-dependent effects on autophagy activation in PDAC cells. In transmission electron microscopy and fluorescence image analysis, we found that autophagic vacuoles were significantly increased in Her-treated cells. Knockdown of ATG5, a key gene in the autophagy pathway, alleviated the activation of autophagy by Her. These results demonstrated that Her induced autophagy in PDAC cells. Intensely activated autophagy could promote cell death. The autophagy inhibitors, BafA1 and HCQ significantly inhibited Her-induced cell death, implying that Her induced autophagic cell death in PDAC cells. Moreover, we showed that Her activated autophagy by increasing the phosphorylation of AMPK and decreasing the phosphorylation of mTOR/p70S6K. Knockdown of AMPKα relieves the autophagic cell death induced by Her. Furthermore, Her concentration-dependently enhanced reactive oxygen species (ROS) generation in PDAC cells. Antioxidants could reduce the phosphorylation of AMPK and suppress autophagic cell death induced by Her. Our study provides evidence for the development of Her as a therapeutic agent for the treatment of pancreatic cancer.

Maximum Value on Arterial Phase Computed Tomography Predicts Prognosis and Treatment Efficacy of Sunitinib for Pancreatic Neuroendocrine Tumours.

PURPOSE: This study was designed to assess the computed tomography maximum (CTmax) value on pretherapeutic arterial phase computed tomography (APCT) images to predict pancreatic neuroendocrine tumours (pNETs) recurrence and clarify its role in predicting the outcome of tumour therapy. METHODS: This retrospective study enrolled 250 surgical patients and 24 nonsurgical patients with sunitinib-based treatment in our hospital from 2008 to 2019. CT images were assessed, the maximum value was defined as "CTmax," and recurrence-free survival (RFS) or progression-free survival (PFS) was compared between a high-CTmax group and a low-CTmax group among patients who underwent surgical resection or nonsurgical, sunitinib-based treatment according to the CTmax cutoff value. RESULTS: In ROC curve analysis, a CTmax of 108 Hounsfield units, as the cutoff value, achieved an AUC of 0.796 in predicting recurrence. Compared with the low-CTmax group, the high-CTmax group had a longer RFS (p < 0.001). Low CTmax was identified as an independent factor for RFS (p < 0.001) in multivariate analysis; these results were confirmed using the internal validation set. The CTmax value was significantly correlated with the microvascular density (MVD) value (p < 0.001) and the vascular endothelial growth factor receptor 2 (VEGFR2) score (p < 0.001). Furthermore, the high-CTmax group had a better PFS than the low-CTmax group among the sunitinib treatment group (p = 0.007). CONCLUSIONS: The tumour CTmax on APCT might be a potential and independent indicator for predicting recurrence in patients who have undergone surgical resection and assessing the efficacy of sunitinib for patients with advanced metastatic pNETs.

Resilience index improves prediction of 1-year decreased quality of life in breast cancer.

BACKGROUND: Resilience is important in cancer survivorship and has great potential to predict long-term quality of life (QoL) in breast cancer. The study was designed to develop a new prediction model to estimate pretest probability (PTP) of 1-year decreased QoL combing Resilience Index (RI) and conventional risk factors. METHODS: RI was extracted from 10-item Resilience Scale Specific to Cancer (RS-SC-10) based on the Principal Component Analysis (PCA). Patients were enrolled from Be Resilient to Breast Cancer (BRBC) and the prediction model was developed based on a sample of 506 consecutive patients and validated in an internal cohort (N1 = 314) and two external cohorts (N2 = 223 and N3 = 189). Integrated Discrimination Improvement (IDI) and Net Reclassification Improvement (NRI) were utilized to estimate the incremental value of RI. RESULTS: RI improved prediction above conventional risk factors. AUC increased from 0.745 to 0.862 while IDI and NRI were 8.39% and 18.44% respectively (P < 0.0001 for all). Five predictors were included in the final model: RI, age, N stage, M stage, and baseline QoL. The new model demonstrated good calibration ability in the internal and external cohorts resulting in C-indexes of 0.862 (95%CI, 0.815-0.909), 0.828 (95%CI, 0.745-0.910), 0.880 (95%CI, 0.816-0.944), and 0.869 (95%CI, 0.796-0.941). CONCLUSION: RI contributed to a more accurate estimation for PTP of 1-year decreased QoL above conventional risk factors and could help optimize decision making of treatment for breast cancer. IMPLICATIONS FOR CANCER SURVIVORS: A promising prognostic indicator of RI could improve QoL-related management in Chinese patients with breast cancer.

Multimodality imaging differentiation of pancreatic neuroendocrine tumors and solid pseudopapillary tumors with a nomogram model: A large single-center study.

Background: Pancreatic neuroendocrine tumors (pNETs) and solid pseudopapillary tumors (SPTs) are two of the most common pancreatic neoplasms with different treatment procedures. However, the broad heterogeneity of pNETs and SPTs in clinical manifestations and radiological features often confuse the presurgical discrimination in clinical practice, and the clinical and molecular differentiation of the two tumors remains elusive to date. We presume that a large and comprehensive study into the multimodality features of pNETs and SPTs is necessary for precise clinical management. Methods: We collected and analyzed the clinicopathological information and multimodality features of nonfunctional pNET and SPT patients, for a total of 631 cases from 2006 to 2021. Univariate analysis of imaging features, including contrast-enhanced computed tomography (CT), magnetic resonance imaging, endoscopic ultrasound (EUS) and nuclear medicine imaging, and clinical characteristics was performed, and CT features and clinical information were integrated to establish a nomogram model. Results: We recruited 354 nonfunctional pNET and 277 SPT patients in our cohort. Regarding demographic information, pNET patients had a lower female percentage (55.4% vs. 72.9%), smaller tumor size (2.8 vs. 4.8 cm), and older age (53.4 vs. 35.3 years). In CT imaging and EUS, pNETs tended to appear as solid and homogenous lesions with strong enhancement intensity. Multifocal lesions, duct dilation, and lymph node (LN) enlargement were more likely to be observed in pNETs, while calcification was more common in SPT lesions. On positron emission tomography (PET)/CT, pNETs exhibited significant sensitivity to somatostatin receptor scintigraphy (SRS), with positive rates of 81.4% and 95% on 99mTc-HYNIC-TOC and 68Ga-DOTATATE PET/CT, respectively, while SPTs were all negative on SRS. Multivariate analysis identifies tumor size, age, enhancement intensity, calcification, and LN enlargement as statistically significant variables. Conclusions: Compared to SPT patients, pNET patients exhibit an older age and smaller tumor size. CT manifestations of strong intensity, LN enlargement, and no calcification could indicate a higher possibility of pNET. Meanwhile, the similarity in the immunohistochemical profile indicates that the two tumors could potentially develop from the same origin.