Seminars In Oncology[JOURNAL]
Sun
200 papers
Physics-informed deep learning sharpens nano diagnostics for elusive pancreatic cancer.
Rahdar A, Mohammadzadeh V, Razzaq S … +6 more , Shirzad M, Fathi-Karkan S, Bakhshi A, Behzadmehr R, Kharaba Z, Ferreira LFR
Semin Oncol · 2026 Feb · PMID 41129854 · Publisher ↗
Pancreatic disease affects over 10% of the world population, and the most dangerous is pancreatic cancer (PC). The disease is mostly of late age of onset, especially in developed countries, and is associated with poor pr...
Pancreatic disease affects over 10% of the world population, and the most dangerous is pancreatic cancer (PC). The disease is mostly of late age of onset, especially in developed countries, and is associated with poor prognosis due to late presentation. Present screening tests like imaging and biomarkers are insensitive for the high-risk group. Invasive and noninvasive imaging modalities are other diagnostic tests with variable accuracy and accompanying risks. Chemotherapy and surgery are the first lines of treatment, but only 15%-20% of patients are eligible for surgery and the rate of recurrence is very high. Emerging technologies, including physics-informed deep learning (PIDL) and artificial intelligence (AI), are improving early detection techniques by evaluating images and synthesizing data more efficiently. Nanomedicine and AI-driven radiomics are individualizing diagnoses, enhancing drug delivery, and tackling tumor microenvironment issues. Hybrid model methodologies are improving prediction precision in oncology research, while computational drug development and liquid biopsy technologies enable early diagnosis and personalized treatment. The amalgamation of AI, imaging, nanomedicine, and physics-informed models has the potential to transform PC diagnostics, enhancing early detection and patient prognoses.
Mapping the epidemiology of cancer-related anemia: A systematic scoping review of global prevalence and incidence.
Elkhalifa D, Lub-de Hooge MN, Jansman FG
Semin Oncol · 2025 Dec · PMID 41046821 · Publisher ↗
Cancer-related anemia (CRA) is a common and debilitating condition among oncology patients, driven by tumor burden, treatment toxicity, nutritional deficiencies, and systemic inflammation. This review aims to synthesize...
Cancer-related anemia (CRA) is a common and debilitating condition among oncology patients, driven by tumor burden, treatment toxicity, nutritional deficiencies, and systemic inflammation. This review aims to synthesize evidence on the global and geographical prevalence and incidence patterns of CRA. A systematic search of PubMed and Embase identified English-language studies on CRA published was performed between 2000 and November 30, 2024. Observational studies and clinical trials reporting CRA prevalence and/or incidence were included. Extracted data covered country, study design, patient demographics, cancer type, anemia classification, and CRA incidence/prevalence rates. The data were then charted by geographical locations. A total of 42 studies, encompassing 65,179 cancer patients across 5 continents and 40 countries, were included. CRA prevalence ranged from 12.8% to 100%, with the highest rates reported in lung (84.2%), pediatric cancers (80.9%), gynecological (62.99%), and gastrointestinal (57.4%) cancers. The composite prevalence of anemia across multiple cancer types and solid tumors was 64.99% and 25.68%, respectively. However, cancer-type-specific analyses often reported higher prevalence rates than composite outcomes, with variations largely influenced by geographical location. Chemotherapy and radiotherapy were consistently associated with increased incidence, with post-treatment anemia prevalence reaching 100% in some cohorts. Regional disparities were noted, particularly in Africa, South America, and the Middle East and North Africa (MENA) region. CRA is a globally prevalent condition, with rates influenced by cancer type, geographic region, and the initiation of chemotherapy or radiotherapy. Future research should prioritize standardized reporting and address regional data gaps.
Corrigendum to "Epidemiology and prevention of gastric cancer: A comprehensive review" [Seminars in Oncology Volume 52 (2025) 152341].
Pradhan SP, Gadnayak A, Pradhan SK … +1 more , Epari V
Semin Oncol · 2025 Dec · PMID 41033962 · Publisher ↗
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Ubiquitin-specific proteases in pancreatic cancer: Molecular regulators of tumor progression and therapy resistance.
Gupta J, Al-Khateeb FN, Zwenal A … +7 more , Alkhathami AG, H M, Kundlas M, Maharana L, Chauhan AS, Mustafa YF, Alnajar MJ
Semin Oncol · 2025 Dec · PMID 40961908 · Publisher ↗
Pancreatic cancer is caused by a complicated set of molecular changes that include genetic mutations and aberrant signaling pathways, which result in tumor growth, metastatic spread, and resistance to therapeutics. Of th...
Pancreatic cancer is caused by a complicated set of molecular changes that include genetic mutations and aberrant signaling pathways, which result in tumor growth, metastatic spread, and resistance to therapeutics. Of the various molecular changes, standard modifying processes, such as ubiquitination and deubiquitination, influence protein levels, cellular localization, and protein function. In this context, ubiquitin-specific proteases (USPs), a primary class of deubiquitinases (DUBs), play a crucial role in regulating the ubiquitin-proteasome system, which controls protein degradation and activity in cells. These USPs can cause the removal of ubiquitin from target proteins, thereby reversing the ubiquitination process. They are key for maintaining cellular homeostasis by regulating the turnover of proteins, including those responsible for signal transduction, cellular processes (such as the cell cycle), and the response to stress events. At the same time, USPs (including USP21, USP13, USP51, and USP22) also affect multiple signaling pathways, including the Wnt, NF-κB, and TGF-β pathways, all of which are involved in the biology of pancreatic cancer. USPs will promote or inhibit cancer-associated pathways that drive proliferation, metastasis, immune evasion, and therapy resistance by stabilizing or destabilizing specific signaling molecules. This review will examine the mechanistic roles of USPs in pancreatic cancer, as well as the tumor behavior and therapeutic resistance that may result from the dysregulation of these proteins. Ultimately, by presenting an opportunity to develop targeted therapies against specific USPs, we hope to emphasize new therapeutic strategies that could positively impact the lives of patients suffering from this aggressive disease.
Metabolism at the core of melanoma: From bioenergetics to immune escape and beyond.
Hsu CY, Ahmed YK, Mohammed S … +5 more , Alghamdi MA, Al-Ghamdi HS, Mohammed JS, Jawad MA, Alsaadi SB
Semin Oncol · 2025 Dec · PMID 40945210 · Publisher ↗
Melanoma is a particularly aggressive type of skin cancer due to its rapid growth and capacity to metastasize. There is substantial metabolic reprogramming in melanoma that is linked to its malignant characteristics, inc...
Melanoma is a particularly aggressive type of skin cancer due to its rapid growth and capacity to metastasize. There is substantial metabolic reprogramming in melanoma that is linked to its malignant characteristics, including therapeutic resistance. This review intended to provide a detailed overview of the central metabolic pathways reprogrammed in melanoma, including the Warburg effect and the complex interactions between glycolysis and oxidative phosphorylation, which ultimately influence energy production, biosynthesis, and adaptation to the tumor microenvironment. We also discuss the molecular pathways that regulate these metabolic pathways and the effect these metabolic processes have on crucial elements of melanoma progression, including invasion, metastasis, and survival during nutrient deprivation and hypoxia. Furthermore, we discuss the importance of metabolism beyond glucose, including glutamine metabolism, changes in lipid metabolism, and alterations in one-carbon and nucleotide biosynthesis, as well as mechanisms critical for the proliferation and survival of melanoma cells. An emphasis is placed on the active metabolic crosstalk between melanoma cells and the immune system within the tumor microenvironment, where melanoma cells utilize nutrient competition and the production of immunosuppressive metabolites to alter and block the function of anti-tumor immune cells, thereby facilitating immune evasion and therapy resistance. Lastly, we critically assess developments targeting melanoma metabolism, including pharmacological inhibition of key metabolic enzymes and pathways, as well as metabolic modulation to enhance the efficacy of conventional and immunotherapies. Although promising, this area is complex and subject to contextual effects and metabolic heterogeneity, indicating that we still have a way to go in annotating robust and clinically relevant metabolic targets. We sought to consolidate current knowledge about melanoma metabolism and highlight the challenges, future directions, and complexity of a potential therapeutic vulnerability in the rapidly evolving field of cancer research.
Application of single-layer continuous duct-to-mucosa pancreaticojejunostomy in oncologic pancreaticoduodenectomy.
Chen Q, Liu F, Yan L … +9 more , Huang X, Wei J, Guo F, Chen J, Lu Z, Wu J, Yin J, Wu P, Jiang K
Semin Oncol · 2025 Dec · PMID 40939225 · Publisher ↗
Pancreaticojejunostomy is a critical step in pancreaticoduodenectomy, and its failure often results in pancreatic fistula. Clinically relevant pancreatic fistula (CRPF) can cause severe complications. This study evaluate...
Pancreaticojejunostomy is a critical step in pancreaticoduodenectomy, and its failure often results in pancreatic fistula. Clinically relevant pancreatic fistula (CRPF) can cause severe complications. This study evaluates the safety and feasibility of single-layer continuous duct-to-mucosa (SCD) pancreaticojejunostomy in preventing CRPF. We prospectively collected baseline characteristics and perioperative data from patients who underwent SCD pancreaticojejunostomy at our center between January and December 2020. A total of 156 patients were included in this study. The mean pancreaticojejunostomy time was 6.5 min, and the mean operation time was 247.6 min. CRPF occurred in 31 patients (19.9%), severe complications (Clavien-Dindo classification ≥III) occurred in 27 patients (17.3%), the mean length of hospitalization was 17.2 days, and the 90-days mortality was 0.0%. SCD pancreaticojejunostomy is an efficient and straightforward technique. It is applicable to various pancreatic conditions and demonstrates favorable clinical outcomes.
Tumor tough, therapy smarter: Rethinking CAR-T for pancreatic cancer.
Guirguis DA, Hasan F, Morris N … +4 more , Alabd A, Tawfik PMS, Pramanik K, Pandey MK
Semin Oncol · 2025 Dec · PMID 40912036 · Publisher ↗
Chimeric antigen receptor (CAR) T-cell therapy has changed how we treat blood cancers but hasn't worked as well for solid tumors like pancreatic ductal adenocarcinoma (PDAC), mainly because these tumors are very aggressi...
Chimeric antigen receptor (CAR) T-cell therapy has changed how we treat blood cancers but hasn't worked as well for solid tumors like pancreatic ductal adenocarcinoma (PDAC), mainly because these tumors are very aggressive and resistant to regular treatments. This review critically examines peer-reviewed studies to chart the evolution of immunotherapy in PDAC, emphasizing the unique barriers to effective CAR T-cell treatment and emerging strategies to overcome them. CAR T-cells that focus on tumor-related markers like mesothelin, HER2, and MUC1 have shown promise in early research models. However, clinical translation is hampered by obstacles such as a dense desmoplastic stroma that restricts T-cell infiltration, antigenic heterogeneity that promotes immune escape, and adverse effects including cytokine release syndrome. Recent innovations include dual-antigen targeting CARs (eg, CEA/MSLN), metabolic reprogramming to enhance T-cell function in nutrient-deprived tumor microenvironments, and stromal-targeting approaches such as fibroblast activation protein (FAP)-specific CARs and heparanase overexpression. Safety enhancements - such as reversible CAR inhibition using Dasatinib and GM-CSF neutralization - are also being explored to mitigate toxicity. Collectively, these advances represent promising strides toward enhancing the efficacy and safety of CAR T-cell therapy for pancreatic cancer. Ongoing research continues to identify new strategies to further refine these therapies, including the exploration of combination treatments with checkpoint inhibitors and novel immunomodulatory agents. As our understanding of the tumor microenvironment deepens, the potential for personalized approaches to CAR T-cell therapy may unlock even greater therapeutic benefits for patients.
Sex-differential responses to immune checkpoint inhibitors across the disease continuum unified by tumor mutational burden.
Zheng M
Semin Oncol · 2025 Dec · PMID 40907130 · Publisher ↗
While the efficacy of immune checkpoint inhibitors (ICIs) in advanced non-small-cell lung cancer (NSCLC) is well-established, sex-based differences in treatment responses remain insufficiently explored. This study examin...
While the efficacy of immune checkpoint inhibitors (ICIs) in advanced non-small-cell lung cancer (NSCLC) is well-established, sex-based differences in treatment responses remain insufficiently explored. This study examines how sex disparities impact ICI treatment outcomes in advanced-stage NSCLC, focusing on the role of tumor mutational burden (TMB) in these differences. This study analyzed data from 174 advanced-stage, chemotherapy-naïve, NSCLC patients treated with ICIs, including PD-1/PD-L1 and CTLA-4 inhibitors, to assess sex differences in treatment response and survival outcomes. Male patients with low TMB (<10 mut/Mb) had worse treatment responses compared to female patients. In contrast, no sex differences were observed in patients with high TMB, where both sexes exhibited similar therapeutic responses. These results suggest that high TMB may reduce the impact of sex on ICI efficacy, with male and female patients showing comparable outcomes. Furthermore, sex disparities in disease progression and overall survival were more evident in low-TMB patients, emphasizing the role of TMB in modulating sex-related differences in immunotherapy outcomes. This study highlights the importance of incorporating both sex and TMB into precision oncology. High TMB appears to equalize treatment responses between sexes, while low TMB may necessitate more personalized treatment strategies, particularly for male patients. Further research into the biological mechanisms underlying these differences is essential to optimize ICI therapies and enhance patient outcomes. Integrating both sex and TMB into clinical decision-making will help to develop more tailored and effective cancer immunotherapy.
Unveiling the role of RAI14 in cancer: Biological significance and translational perspectives.
Chong ZX
Semin Oncol · 2025 Dec · PMID 40902302 · Publisher ↗
Retinoic acid-induced protein 14 (RAI14) is an actin-binding protein that regulates actin dynamics, cell adhesion, and migration. RAI14 dysregulation has been reported to facilitate the development of at least 10 tumor t...
Retinoic acid-induced protein 14 (RAI14) is an actin-binding protein that regulates actin dynamics, cell adhesion, and migration. RAI14 dysregulation has been reported to facilitate the development of at least 10 tumor types based on the findings from over 20 original research articles. This review article aims to fill in the gap in the literature by providing a comprehensive summary of the putative tumor-regulatory roles of RAI14 in different cancers. Overall, RAI14 can affect protein kinase B (AKT), mammalian target of rapamycin, yes-associated protein/Hippo, apoptosis, and epithelial-to-mesenchymal transition activities to promote tumorigenesis. Several noncoding RNAs like miR-23b-3p and AFAP1-AS1 can directly or indirectly affect RAI14 expression to control its tumor-modulatory function epigenetically. Additionally, RAI14 tissue or serum level are overexpressed in at least seven human tumors, including breast, gastrointestinal, genitourinary, and brain cancers. This gives RAI14 the translational potential as a diagnostic or prognostic biomarker. Targeting RAI14 as a cancer antigen can also potentially help halt tumor progression. Future large-scale trials are needed to confirm the tumor-regulatory role of RAI14 in human cancer and to evaluate the sensitivity, reliability, and accuracy of using this target as a biomarker or therapeutic target.
Purine metabolism in tumorigenesis and its clinical implications.
Lu Z, Li J, Liu Y … +5 more , Li H, Sun Y, Geng R, Song J, Liu J
Semin Oncol · 2025 Dec · PMID 40902301 · Publisher ↗
Metabolic reprogramming constitutes a hallmark of malignant neoplasms. Purine metabolism emerges as a pivotal regulator in cellular metabolic networks through multiple mechanisms, including dysregulation of de novo biosy...
Metabolic reprogramming constitutes a hallmark of malignant neoplasms. Purine metabolism emerges as a pivotal regulator in cellular metabolic networks through multiple mechanisms, including dysregulation of de novo biosynthesis/salvage pathway coordination, adenosine-mediated immunosuppressive microenvironment formation, and collective contributions to tumorigenesis and malignant progression. During metastatic progression, purine metabolism reinforces tumor cell plasticity through mitochondrial energy regulation and modulation of cell cycle checkpoints (eg, G1/S transition). These mechanistic revelations have positioned purine metabolism-targeting strategies as promising oncotherapeutic candidates. This review methodically analyzes (1) purine metabolic pathways and their regulatory dynamics, (2) adenosine-mediated pathophysiological interactions, and (3) the synergistic impacts of these pathways in malignant transformation. We propose a unified mechanistic framework that clarifies oncogenic purine metabolic rewiring while evaluating translational potential through three clinical dimensions: pathogenesis elucidation, diagnostic biomarker discovery, and targeted therapeutic development. This comprehensive synthesis aims to advance precision oncology through mechanistic insights and therapeutic innovation.
Application prospects of tumor vaccines for pancreatic cancer: From TAAs to TSAs and combination strategies.
Lu Z, Zhu W, Liu X
Semin Oncol · 2025 Oct · PMID 40839910 · Publisher ↗
Pancreatic cancer, a highly aggressive malignancy of the digestive system, exhibits therapeutic resistance due to its immunosuppressive tumor microenvironment (TME) and early metastatic potential. Cancer vaccines targeti...
Pancreatic cancer, a highly aggressive malignancy of the digestive system, exhibits therapeutic resistance due to its immunosuppressive tumor microenvironment (TME) and early metastatic potential. Cancer vaccines targeting tumor-associated antigens (TAAs) or tumor-specific antigens (TSAs) have emerged as promising immunotherapeutic strategies. TAA-based vaccines demonstrate T cell activation and tumor suppression in preclinical models, yet face limitations from antigen heterogeneity and immunosuppressive TME. TSA-directed vaccines, exemplified by personalized mRNA vaccines incorporating whole-exome sequencing-selected neoantigens, achieved long-term recurrence-free survival in 50% of vaccinated patients during phase I/II trials, with phase III data supporting synergistic efficacy when combined with chemotherapy and programmed death receptor 1 (PD-1) inhibitors. KRAS-targeted vaccines address common mutations (e.g., G12D, G12V) to broaden applicability. This review presents an updated summary of current tumor vaccine types, mechanisms, and clinical implications, while analyzing how combination therapies remodel TME infiltration and reverse T cell exhaustion to significantly improve survival outcomes. The discussion also addresses existing challenges and proposes future directions in pancreatic cancer vaccine development.
The effects of microbiota-derived short-chain fatty acids on T lymphocytes: From autoimmune diseases to cancer.
Saadh MJ, Allela OQB, Ballal S … +7 more , Mahdi MS, Chahar M, Verma R, Al-Hussein RKA, Adil M, Jawad MJ, Al-Nuaimi AMA
Semin Oncol · 2025 Oct · PMID 40834607 · Publisher ↗
Short-chain fatty acids (SCFAs), acetate, propionate, and butyrate, are the microbial metabolites that have significant functions in host immune modulation, especially T lymphocyte function. Implication by recent evidenc...
Short-chain fatty acids (SCFAs), acetate, propionate, and butyrate, are the microbial metabolites that have significant functions in host immune modulation, especially T lymphocyte function. Implication by recent evidence indicates SCFAs regulate T-cell growth, differentiation, metabolism, effector function, and apoptosis through histone deacetylase (HDAC) inhibition, G-protein-coupled receptor (GPCR) signaling, and metabolic reprogramming processes. Butyrate, for example, enhances regulatory T cell (Treg) and Interleukin 10 (IL-10)-producing T helper 1 (Th1) cell differentiation as well as context-dependent regulation on T helper 17 (Th17) cell development. SCFAs also impact cytotoxic CD8+ T cells through augmented production of IFN-γ and memory formation, which enhances antiviral and antitumor immunity. SCFAs reprogram T-cell metabolism through enhanced acetyl-CoA, mechanistic target of rapamycin (mTOR) signaling, and fatty acid oxidation (FAO), thus promoting the unique metabolic requirements of effector and memory T-cell subsets. In addition, SCFAs induce apoptosis of activated T cells through the Fas upregulation by inhibiting HDAC1. SCFA dysregulation plays a role in disease and autoimmune disorders like type 1 diabetes and rheumatoid arthritis, whereas therapeutic supplementation reduces inflammation and immune tolerance. SCFAs also amplify the antitumor effect of immune checkpoint inhibitors (eg, anti-programmed cell death protein 1 (anti-PD-1)) in cancer by driving CD8+ T-cell activation, infiltration, and Interferon gamma (IFNγ) production, partially through the transcriptional regulator Inhibitor of DNA binding 2 (ID2). Significantly, tissue- and disease-specific differential expression and functional implication of SCFA receptors (eg, GPR43, GPR41, GPR109A) emphasize the complexity of SCFA-mediated signaling. In conclusion, the current review emphasizes the multifunctional role of microbiota-derived SCFAs in T lymphocyte biology and their therapeutic potential in cancer, infection, and autoimmune diseases.
Deregulated cell cycle control: The interplay between non-coding RNAs and cyclin-dependent kinases in tumorigenesis.
Hsu CY, Almajidi YQ, Al-Hakeem MA … +7 more , Alshahrani MY, Nabil W, Jayakumar SS, SinglaI S, Al-Khafaji ZA, Hussein AR, Al-Mashhadani ZI
Semin Oncol · 2025 Oct · PMID 40803047 · Publisher ↗
Cyclin-dependent kinases (CDKs) are a group of serine/threonine kinases that are at the center of cell cycle progression. Dysregulated CDK activity, found in a range of human cancers, leads to uncontrolled cell growth an...
Cyclin-dependent kinases (CDKs) are a group of serine/threonine kinases that are at the center of cell cycle progression. Dysregulated CDK activity, found in a range of human cancers, leads to uncontrolled cell growth and development. Non-coding RNAs (ncRNAs), which include microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), are emerging as critical regulators of gene expression and cellular processes, playing an important and often complex role in cancer development and progression. The purpose of this review is to organize knowledge about the interactions of ncRNAs with CDKs, contribution to cancer biology, and to discuss not only the different ways miRNAs target and downregulate CDKs mRNA, leading to inhibition of cell cycle progression and acting as tumor suppressors, but in the case of some miRNAs alter CDK activity as oncogenes by directly upregulating CDK expression or more frequently suppressing the expression of the canonical CDK inhibitors (p21 and p27). Moreover, long non-coding RNAs (lncRNAs) can regulate CDKs through a variety of mechanisms, such as functioning as molecular sponges by absorbing miRNAs that target CDK proteins as miRNA sponges, modulating CDK protein abundance and/or activity indirectly or directly (i.e., the direct interaction with the CDK proteins can potentially invoke an ability to regulate their stability, etc.). Circulating RNAs (circRNAs) also primarily modulate CDK levels and act as inhibitors of the appropriate CDK targeted by a miRNA sponge, potentially through direct interaction with a CDK. Overall, while our understanding of the ncRNA-CDK network is far from complete, the complexities surrounding ncRNA-CDK oncogenic developments and the ability to target these pathways offer significant promise in the harsh realities of cancerogenesis and further therapeutic interventions to fashion more precise cancer therapies that antagonize aberrant cell cycle progression in cancer subtypes.
Psoas muscle depletion correlates with poor prognosis and compromised immunity in resectable gastric cancer: A multicenter study.
Zhou H, Zhong L, Jin Z … +7 more , Hou X, Tang H, Yang S, He Y, Song W, Zhang C, Wei Z
Semin Oncol · 2025 Oct · PMID 40795602 · Publisher ↗
Sarcopenia, assessed by the psoas muscle index (PMI), is characterized with the loss of skeletal muscle mass and strength, and has gained growing attentions in the field of cancers. However, its role in gastric cancer (G...
Sarcopenia, assessed by the psoas muscle index (PMI), is characterized with the loss of skeletal muscle mass and strength, and has gained growing attentions in the field of cancers. However, its role in gastric cancer (GC), especially in patients received gastrectomy, remains underexplored. This multicenter retrospective study examined 439 patients with resectable GC to assess the prognostic significance of sarcopenia, measured by PMI and PMI change rate (PMICR), while also exploring potential links with tumor immunity. Kaplan-Meier analysis revealed that low PMICR was significantly associated with worse survival outcomes in all patient cohorts. Further multivariate Cox analysis identified PMICR (hazard ratio: 2.80, 95% CI: 1.73-4.56), but not baseline PMI-as an independent predictor of overall survival. Immunologically, low PMICR patients exhibited decreased tertiary lymphoid structure density and reduced tumor-infiltrating lymphocytes (CD3+ T cells and CD20+ B cells). The developed nomogram incorporating PMICR showed superior prognostic performance versus TNM stage, with concordance indices of 0.821 (95% CI: 0.789-0.853), 0.800 (95% CI: 0.753-0.847), and 0.816 (95% CI: 0.743-0.889) for training, internal validation, and external validation cohorts, respectively. These results suggested that PMICR, as a measure of sarcopenia, more accurately predicted survival outcomes and might be associated with immune status in resectable GC patients. Moreover, the newly developed nomogram demonstrated high accuracy in predicting prognosis.
Overexpression of CAD in stomach adenocarcinoma tissues and its clinical significance.
Wang S, Xing H, Long M … +6 more , Zhou M, Wang Z, Hou B, Mo S, Na D, Bu S
Semin Oncol · 2025 Oct · PMID 40795601 · Publisher ↗
Stomach adenocarcinoma (STAD) is one of the deadliest malignant tumors worldwide. Carbamoyl-phosphate synthetase 2 (CAD) expression is essential for categorizing and detecting STAD initiation and development. We explored...
Stomach adenocarcinoma (STAD) is one of the deadliest malignant tumors worldwide. Carbamoyl-phosphate synthetase 2 (CAD) expression is essential for categorizing and detecting STAD initiation and development. We explored the differential expression of genes (DEGs) affected by CAD overexpression and subsequently revealed the classification module of CAD-based scoring sets using weighted gene co-expression network analysis (WGCNA). Subsequently, enrichment analysis of biological functions and signaling pathways in clinically significant modules was conducted. We constructed a CAD-based clinical scoring model using univariate and multivariate Cox regression analyses. In addition, by using immune cell infiltration analysis, we investigated the interaction between CAD-based score and the immune microenvironment, identified upstream regulatory factors, including RNA binding proteins (RBPs), that affect the transcription of the STAD-related CAD-based score, and explored potential drug targets. We identified 4,977 abnormal regulatory genes related to CAD in STAD, among which the module genes most related to CAD were significantly enriched in cancer-related signaling pathways, such as VEGF, MAPK and TGF-beta signaling pathway. The CAD-based scores, T and N were identified as independent prognostic factors for STAD patients. We also found that under the influence of high expression of CAD, the infiltration level of most immune cells is lower, such as CD4 T cells and Tfh, and CAD has an inhibitory effect on the infiltration of certain immune cells. Notably, the potential drug targets PDHB and NDUFB6 are upstream regulatory factors in STAD. This study explored the role of highly expressed CAD-related genes in STAD and explored the tumorigenesis and progression of this disease. This research identified potential diagnostic and prognostic drug targets and provided new insights into the molecular mechanisms of STAD.
Deciphering autophagy signaling in cancer: A paradigm shift from molecular classifications to clinical innovations.
Altalbawy FMA, Theab EY, Sanghvi G … +7 more , Roopashree R, Kashyap A, Al-Hetty HRAK, Gayathri S, Panigrahi R, Mustafa YF, Yasin HA
Semin Oncol · 2025 Oct · PMID 40782541 · Publisher ↗
The intracellular breakdown process known as autophagy occurs when cells experience adverse conditions, such as organelle damage, the presence of abnormal proteins, hypoxia stress, low energy levels, or nutritional depri...
The intracellular breakdown process known as autophagy occurs when cells experience adverse conditions, such as organelle damage, the presence of abnormal proteins, hypoxia stress, low energy levels, or nutritional deprivation. The autophagic process begins by forming autophagosomes, which then merge with lysosomes to recycle degraded materials. Autophagy functions in multiple ways to affect cancer development and treatment outcomes. Tumor cells with low autophagy levels may exhibit anti-tumor effects during cancer initiation because their connection to malignant transformation is possible. The promotion of autophagy appears beneficial for cancer prevention in this context. The survival of cancer cells through increased autophagy enables tumor growth in existing tumors by allowing them to overcome metabolic and treatment-related challenges. Research indicates that blocking autophagy through the use of drugs or genetic methods makes cancer cells more susceptible to chemotherapy, radiation, and targeted therapies, suggesting that inhibiting the autophagic system may be a promising approach to enhance treatment. Excessive autophagy activation could be a therapeutic approach to manage cancer cells that resist cell death. The successful treatment of cancer requires an understanding of autophagy's dual nature. This review examines potential therapeutic strategies for tumors by analyzing autophagy-related signaling pathways and the essential factors that influence cancer development.
Antibody treatments for digestive cancers: Past, present, and future.
Dadi I, Mazard T, Schmitt LM … +4 more , Chastel T, Turtoi A, Poul MA, Pattingre S
Semin Oncol · 2025 Oct · PMID 40773999 · Publisher ↗
Gastrointestinal (GI) malignancies accounted for more than one in four cancer cases (4.8 million cases) in 2020. Among these, around 37% were colorectal followed by gastric (21%) and liver cancers (18%). Notably, GI canc...
Gastrointestinal (GI) malignancies accounted for more than one in four cancer cases (4.8 million cases) in 2020. Among these, around 37% were colorectal followed by gastric (21%) and liver cancers (18%). Notably, GI cancers are responsible for nearly one-third of cancer-related mortality (3.4 million deaths worldwide). For decades, treatment relied primarily on conventional cytotoxic chemotherapies, which target rapidly dividing malignant cells but also cause significant harm to healthy tissue. Recent biotechnological advances enhanced our understanding of cancer biology, leading to the identification of specific molecular alterations and the development of new drugs, known as "targeted therapies." These therapies include two major categories: small molecule kinase inhibitors (SMKIs), which inhibit dysregulated intracellular kinases, and monoclonal antibodies (mAbs), able to interfere with extracellular ligands, membrane receptors, or membrane-bound proteins. This review aims to summarize recent advancements in the treatment of GI cancers using mAbs. We provide an overview of clinically approved mAbs in GI cancers, detailing their targets, mechanisms of action, and limitations. We differentiate between mAbs that directly target cancer cells and those that act on the tumor microenvironment (TME). Additionally, we discuss developments and technological optimizations used to improve the efficacy and specificity of these therapies.
Lactylation in radiosensitivity regulation: Mechanistic insights and recent advances.
Zhu C, Tian M, Di X … +6 more , Liu J, Chen H, Xu L, Liu Y, Sun X, Zhang Z
Semin Oncol · 2025 Oct · PMID 40716123 · Publisher ↗
Lactylation, as a novel post-translational modification, has gained a lot of attention in the biomedical field in recent years. Lactylation is not only related to cellular metabolism but also increasingly prominent in th...
Lactylation, as a novel post-translational modification, has gained a lot of attention in the biomedical field in recent years. Lactylation is not only related to cellular metabolism but also increasingly prominent in the tumor microenvironment, particularly in regulating radiation sensitivity. This review aims to explore the potential connection between lactylation modification and the regulation of radiation sensitivity. Current research shows that lactylation might be crucial in how tumor cells respond to radiotherapy by influencing energy metabolism, gene expression, and cell signaling. However, despite preliminary studies revealing the association between lactylation and radiation sensitivity, the understanding of its specific mechanisms remains insufficient, necessitating more systematic research to elucidate this process. Therefore, by analyzing the biological basis of lactylation modification, its role in tumor metabolism, and its relationship with radiotherapy, we summarize the importance and application prospects of lactylation in tumor treatment, providing direction for future research.
Germline mutations in B-cell non-Hodgkin lymphoma-associated hemophagocytic lymphohistiocytosis (LA-HLH) and patient outcomes.
Zhong X, Zhu X, Ma X … +10 more , Zhou L, Luo X, Li P, Ding Y, Fu J, Bo J, Yang M, Liang A, Zeng Y, Xiu B
Semin Oncol · 2025 Oct · PMID 40700998 · Publisher ↗
Lymphoma-associated hemophagocytic lymphohistiocytosis/syndrome (LA-HLH/LAHS) represents the most prevalent form of malignancy-associated HLH and is associated with an exceptionally poor prognosis. Emerging evidence impl...
Lymphoma-associated hemophagocytic lymphohistiocytosis/syndrome (LA-HLH/LAHS) represents the most prevalent form of malignancy-associated HLH and is associated with an exceptionally poor prognosis. Emerging evidence implicates germline mutations as potential contributors to hematologic abnormalities, suggesting a genetic predisposition in affected individuals. We conducted whole-exome sequencing (WES) on a cohort of 12 LA-HLH patients, with detailed analysis of 3 representative cases exhibiting coexisting genetic disorders. These cases were comprehensively evaluated for their clinical management strategies and therapeutic outcomes. Our study revealed that gene mutations were detected in 6 patients (6/12), including 2 had somatic mutations, 3 had germline mutations, and 1 had both somatic and germline mutations. Among the 4 patients harbored germline mutations, 3 were diagnosed with concurrent genetic disease. Most patients (11/12) responded to immunochemotherapy for a short time and then progressed or relapsed, even after autologous hematopoietic stem cell transplantation (ASCT). Interestingly, two patients received CAR-T-cell therapy and achieved extremely good responses. One patient received CD19 CAR-T-cell infusion and had a PFS of 26 months. The other patient received double CAR-T infusions and has remained in complete remission for more than 2 years (until now). This study proposes that LA-HLH may constitute a novel genetic subtype of lymphoma. Systematic genetic sequencing should be prioritized to guide precision treatment approaches in selected cases, including immunotherapies such as CAR-T-cell therapy. These insights redefine our understanding of LA-HLH pathogenesis and clinical intervention strategies.
Deciphering the prognostic value and immunotherapeutic strategy of aggrephagy in melanoma: Integrating single-cell sequencing and machine learning.
Li Z, Xie J, Li L … +4 more , He Y, Chen W, Dai H, Zhao S
Semin Oncol · 2025 Oct · PMID 40695191 · Publisher ↗
This study aimed to investigate the role of aggrephagy in cutaneous melanoma (CM) and explore its potential as a biomarker for prognosis and therapeutic targeting. We utilized single-cell sequencing technology and machin...
This study aimed to investigate the role of aggrephagy in cutaneous melanoma (CM) and explore its potential as a biomarker for prognosis and therapeutic targeting. We utilized single-cell sequencing technology and machine learning algorithms to analyze melanoma transcriptome data from the TCGA database and validated our findings using 3 independent datasets from the GEO database. By employing enrichment scoring in single-cell sequencing, we identified characteristic expression patterns of different cell types involved in aggrephagy and constructed an aggrephagy-related signature (ARS). We further evaluated the association of ARS with clinical features, immune cell infiltration, tumor mutational load (TMB), and immune checkpoint gene expression. Additionally, we conducted in vivo experiments by knocking down TPX2, the most critical oncogene in ARS, using shRNA and assessed its effects on tumor proliferation and T-cell growth via subcutaneous tumor formation assays and flow cytometry in mice. The ARS demonstrated robust prognostic predictive power across multiple datasets, with higher ARS scores associated with poorer overall survival (OS) and lower levels of immune cell infiltration. Patients with low ARS scores were more likely to benefit from immune checkpoint inhibitor therapies, while those with high scores exhibited increased sensitivity to 2 common chemotherapeutic agents. Compared to published melanoma prognostic models, our ARS showed higher accuracy and stability. The construction of an ARS-related nomogram further facilitated more accurate clinical decision-making. In vivo experiments confirmed that TPX2 knockdown inhibited tumor proliferation and enhanced T-cell growth, highlighting its critical role in CM progression. Our study highlights the complex functions of the aggrephagy-related signature in cutaneous melanoma, underscoring its potential as a therapeutic target and a valuable tool for prognostic assessment.
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