During the diagnosis and treatment of non-small cell lung cancer (NSCLC), detecting the risk of its recurrence in an early phase is still challenging. Recent studies have investigated the radiomics-based machine learning (ML) models for detecting the risk of recurrence in NSCLC. However, there is still insufficient systematic evidence to prove its efficiency.

Pulmonary fibrosis (PF) significantly increases the risk of lung cancer (LC), but the mechanisms underlying this transition remain unclear. This overview positions macrophage heterogeneity as a central node within the PF-LC continuum. First, we describe important subpopulations of profibrotic and pro-tumor macrophages, including SPP1+, MERTK+, TREM2+, and MARCO+ cells, using high-resolution spatial and single-cell omics technologies. Next, we analyze the fundamental mechanisms that determine their function: the fibrotic microenvironment (e.g., extracellular matrix stiffness, hypoxia) induces profound metabolic reprogramming (e.g., Warburg effect, lipid peroxidation) and stabilizes epigenetic memory (e.g., DNA methylation, histone modifications), locking them into a pathogenic state. This reprogramming occurs through two main pathways: (1) metabolic reprogramming, characterized by aerobic glycolytic conversion and dysregulated lipid metabolism, which stimulates both pathogenic functions and suppression of T cell activity; (2) Epigenetic modifications, including stabilized alterations in DNA methylation, histone modifications, and superactivator patterns, which maintain cells in a tumor-promoting phenotype. As central nodes of communication, these macrophages interact pathologically with fibroblasts and epithelial cells through secreted factors and extracellular vesicles, forming self-reinforcing feedback loops that promote disease progression. We are studying the crucial role of new technologies, particularly multi-omic spatial models and high-precision organoids, in fostering mechanistic discoveries. These discoveries pave the way for new macrophage-focused therapeutic strategies, including the precise stratification of patients using biomarkers from liquid biopsies (such as soluble SPP1 and MARCO) and the development of targeted drug delivery systems for the selective modulation of macrophage function, thus establishing a new paradigm for therapeutic interventions in pulmonary fibrosis with concomitant lung cancer.

The tumor microenvironment (TME) exerts significant metabolic limitations that influence the activity of invading immune cells. Among them, macrophages and natural killer (NK) cells are essential for coordinating anti-tumor immunity; however, the metabolic conditions of solid tumors have a significant impact on their functional states. Emerging evidence indicates that metabolic competition and nutrition availability regulate the dynamic interactions between these two innate immune populations, eventually influencing immune activation, suppression, and tumor growth. In this review, we discuss how key metabolic factors, including glucose depletion, lipid metabolism, hypoxia, and lactate accumulation, reshape NK cell activity and macrophage polarization in the TME. We emphasize how cytokine signaling and spatial organization within tumors influence NK-macrophage interactions, resulting in either synergistic anti-tumor responses or immunosuppressive networks. Finally, we explore novel therapeutic approaches designed to target metabolic pathways to restore NK cell function and reprogram macrophages toward pro-inflammatory phenotypes. Understanding the metabolic regulation of NK-macrophage interactions could provide new opportunities to improve immunotherapy efficacy in solid tumors.

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract, with its pathogenesis primarily linked to activating mutations in the KIT or platelet derived growth factor receptor alpha (PDGFRA) genes. Surgical resection remains the standard curative treatment for localized GIST; however, ~50% of patients eventually develop recurrence or metastasis. Since the introduction of imatinib in the early 21st century, the management of metastatic GIST has shifted from solely surgical intervention to a systemic, chronic disease management model centered on tyrosine kinase inhibitors (TKIs). However, during the course of treatment, most patients develop drug resistance. Despite the transformative impact of TKIs, some critical clinical challenges remain unresolved. Intratumoral heterogeneity, in particular, poses a significant obstacle, as tumors often comprise diverse populations of cells with varying genetic and molecular profiles. This diversity means that while some subclones may initially respond well to TKI therapy, others harboring inherent or acquired resistance mutations can continue to proliferate, ultimately leading to treatment failure. Additionally, the limited durability of TKIs responses, even in tumors initially sensitive to treatment, remains a pressing concern. Moreover, the lack of curative systemic options for advanced GIST, along with adverse drug reactions, underscores the unmet needs within this patient population. These challenges underscore the necessity of this review, which discusses current standard drug treatment strategies for advanced GIST, including sequential TKIs therapy and investigations into mechanisms of drug resistance. Finally, the review explores precise and actionable future directions for GIST drug development and clinical management, including mutation-stratified therapeutic sequencing, rational TKI-based combination regimens, and circulating tumor DNA (ctDNA)-guided real-time treatment monitoring and resistance surveillance.

Protein S-palmitoylation is a highly conserved posttranslational lipid modification that occurs on cysteine residues and critically influences protein maturation, subcellular localization, trafficking, and stability. Owing to its unique reversibility and dynamic nature, S-palmitoylation plays a pivotal role in cancer. This review comprehensively summarized the expression profiles and distribution of key cancer-related S-palmitoylation enzymes in recent years. Importantly, we highlight the specific mechanisms by which the dual states of palmitoylation and depalmitoylation function as a dynamic regulatory axis during the transformation of cancer cells into cancer stem cells and during the transition from a normal tissue environment to a tumor microenvironment. Furthermore, we discussed emerging therapeutic strategies targeting S-palmitoylation, including the development of specific inhibitors and competitive blockade of substrate-binding sites, which offer additional insights into the translational potential of S-palmitoylation as a therapeutic target for cancer.

The intratumoral microbiota, as an important component of the tumor microenvironment (TME), impact tumor progression by regulating the arginine-ornithine metabolic axis. It has become a new frontier in tumor research. Arginine is a crucial amino acid in TME, and its metabolites, ornithine and polyamines, directly promote tumor proliferation and induce immunosuppression. Intratumoral microbiota mainly exert their effects through two direct pathways: 1) arginine depletion, such as Streptococcus in gastric cancer. Specific intratumoral microbiota highly express arginine deiminase (ADI) or arginase (Arg) to consume arginine in the TME, leading to T cell dysfunction and enhancing immunosuppressive cells. 2) Ornithine/polyamines supplement, such as fusobacteria in esophageal cancer produce putrescine. The microbiota converts arginine into ornithine, which is then synthesized into polyamines, directly stimulating tumor cell proliferation and reshaping the immunosuppressive TME. Additionally, the metabolic products from the microbiota like short-chain fatty acids (SCFAs) and indole substances, can amplify these effects through signaling pathways including G protein-coupled receptor 43 (GPR43) and aryl hydrocarbon receptors (AHR). The regulation of intratumoral microbiota-arginine metabolism axis has a "double-edged sword" characteristic, relying on the metabolic dependence of the different tumors, which provides a basis for precise treatment. Furthermore, strategies targeting the axis present great potential, including Arg1 inhibitors (CB-1158) in combination with immunotherapy, engineered probiotics to supply arginine and inhibit polyamine synthesis in situ within the TME. These advancements also indicate there is enormous progress from exploring the intratumoral microbiota-metabolism interaction to developing novel tumor microecological therapies.

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) represent a diverse group of tumors, ranging from well-differentiated neuroendocrine tumors to poorly differentiated neuroendocrine carcinomas. Current biomarkers for GEP-NENs are weak and lack sufficient sensitivity and specificity, complicating diagnosis and prognosis. Alpha-fetoprotein (AFP), a well-established biomarker in other cancers, has been reported as a potentially useful biomarker also for GEP-NENs, but its clinical relevance remains unclear. This narrative review evaluates AFP's role in GEP-NENs.

NOL1/NOP2/SUN domain family member 2 (NSUN2), a member of the RNA methyltransferase family responsible for catalysing 5-methylcytosine (m5 C) modifications, has been increasingly recognized as a key regulatory factor in the initiation and progression of cancer. A growing body of evidence indicates that NSUN2 is aberrantly expressed in multiple malignancies, such as hepatocellular carcinoma, breast cancer, and gastric cancer, where its overexpression is frequently associated with unfavourable clinical outcomes, increased tumour aggressiveness, and resistance to therapy. Through its m5C modification activity, NSUN2 influences RNA stability, translational efficiency, and molecular interaction networks, thereby modulating critical oncogenic signalling pathways, including Wnt/β-catenin, PI3K/AKT, and epithelial-mesenchymal transition (EMT). Moreover, NSUN2 has been shown to interact with non-coding RNAs and epigenetic regulatory factors, contributing to the remodelling of the tumour microenvironment and facilitating immune evasion. Although NSUN2 is predominantly characterized by its tumour-promoting functions, emerging studies also suggest context-specific tumour-suppressive roles, highlighting its functional complexity in cancer biology. This review aims to summarize recent advances in understanding the molecular mechanisms underlying NSUN2 function, its clinical significance, and its potential as a biomarker or therapeutic target, while also discussing the challenges in translating these findings into clinical practice. A deeper understanding of NSUN2's diverse roles in carcinogenesis may provide novel insights into RNA epigenetics and inform the development of innovative strategies for cancer diagnosis and treatment.

This review summarizes the latest advancements in electrochemical biosensors for the detection of circulating tumor cells (CTCs). As a core component of liquid biopsy, CTCs are highly valuable for tumor diagnosis and treatment. However, conventional detection methods often fail to meet clinical requirements due to limitations such as low sensitivity and heavy reliance on biomarkers. Electrochemical sensors address these challenges by immobilizing biorecognition elements on electrode interfaces, converting CTCs binding events into quantifiable electrical signals. This approach enables high-sensitivity detection (at the single-cell level), rapid response, and portability. The review systematically explores two key optimization strategies: (1) surface modification for antifouling (e.g., zwitterionic materials, polyethylene glycol layers) and (2) signal transduction strategies (e.g., aptamer-mediated nucleic acid amplification, nanomaterial-based signal amplification), which significantly enhance detection specificity and sensitivity. Furthermore, the review evaluates the clinical utility of this technology in early diagnosis and treatment monitoring, while also discussing challenges such as standardization and clinical translation. This review provides theoretical and technical insights for the development of systematically exploring next-generation high-performance liquid biopsy platforms for cancer.

Retinoblastoma (RB) is typically associated with highly penetrant pathogenic sequence variants (PSVs) in the RB1 gene; however, some families exhibit low penetrance RB (LPRB). We aimed to determine the penetrance rate and identify genetic and clinical characteristics of LPRB. To that end two cohorts were analyzed: 250 genetically confirmed LPRB cases identified through systematic literature review and 78 classical germline RB (CGRB) from three international centers- Thailand, Korea, and Israel. Penetrance rate was estimated as the proportion of affected individuals among RB1 PSV carriers. Multivariate models assessed parent-of-origin effects and predictors of penetrance. PSVs were annotated with Combined Annotation Dependent Depletion (CADD) scores and mapped to pRB structural domains. LPRB penetrance ranged from 50% (125/250, non-age-adjusted, CI [43.8%-56.2%]) to 64% (125/196, age-adjusted, CI [56.8%-70.2%]). Paternal inheritance of RB1 PSV was associated with a significantly increased risk of LPRB in offspring (OR = 6.24; P < 0.0001). Clinically, LPRB were significantly more likely than CGRB to present with unilateral disease (OR = 9.3, P < 0.0001), diagnosed at an older age (13 Vs 6.5 months, P = 0.01), and affect males (OR = 2.4, P = 0.03). LPRB-associated PSVs showed lower CADD scores (OR = 1.5; P = 0.0008), indicating lower predicted pathogenicity, and were enriched in pRB's N- or C-terminal domains (OR = 3.2; P = 0.007), consistent with hypomorphic effects. In conclusion, LPRB shows a 50-64% penetrance rate, more likely to be paternally inherited, have unilateral presentation, and associated with hypomorphic RB1 PSVs in the terminal pRB regions. These findings support retitling 'low penetrance RB' to 'medium penetrance RB'.

Cancer biology is a constantly evolving field of study due to the dynamic and complex nature of biological systems. The unique role of in vitro assays in cell biology has led to numerous transformations in our understanding of the functional and structural details of the cells and tissues that comprise these systems. However, the traditional monolayer assays have been reported to fall short of the in vivo physiology of cells. This has led to the development of 3D cell models, such as spheroids and organoids, that aim to recapitulate the intricate structural and functional behaviour of in vivo tumours. This review describes passive methods of spheroid formation (scaffold-free and scaffold-based) and the limitations that have driven the development of engineered active design methods to increase the physiological relevance of the model. Traditional assays need to be modified to evaluate these models, accounting for their architecture, density, and microenvironment gradients. Current developments in performing 3D cell assays include increased reagent concentration and incubation periods; however, many protocols still require single-cell analysis. We present a review of assay developments that maintain the spatial and contextual information that makes the 3D models physiologically relevant. Additionally, we introduce the advances in microscopy techniques that provide deeper visualisation of these models.

Background and objectives Diffuse large B-cell lymphoma presents a significant challenge due to its high rate of treatment failure in 40% of patients. In this study we screened microRNAs as biomarkers in chemotherapy non-responding patients, to allow their early prognostication. Methods In the exploratory phase, whole transcriptome microRNA profiling was conducted on 10 diffuse large B-cell lymphoma cases. Three patients achieved complete remission, while seven had refractory or relapsed disease. The differentially expressed miRNAs were validated in 41 retrospective, treatment-naive diffuse large B-cell lymphoma biopsies, including the original 10 cases. Additionally, 33 cases with paired biopsy and plasma samples were prospectively evaluated using qRT-PCR to correlate miRNA expression with clinical outcomes. Functional validation to identify downstream pathways was done by knocking down identified miRNAs in JM-1 cells by semi-quantitative proteomics. Results miR-193b-5p, miR-1307-5p, and miR-671-5p expression were downregulated in refractory/relapsed diffuse large B-cell lymphoma biopsies. Plasma miRNA levels did not reflect prognosis. In vitro proteomics showed their impact on key oncogenic pathways, revealing significant enrichment of replication and transcription-related proteins. Interpretation and conclusions The expression of miR-193b-5p, miR-1307-5p, and miR-671-5p miRNAs in diffuse large B-cell lymphoma tissues may serve as predictive biomarkers.

Background and objectives Ovarian carcinoma is one of the most lethal carcinomas among females. Its high prevalence and shorter 5-year survival rate is due to the fact that most of the cases are diagnosed at later stages. This highlights the importance of early diagnosis through reliable biomarkers. We studied the diagnostic role of SOX9 protein in ovarian carcinoma and its diagnostic ability. The primary objective was to compare the level and clinical relevance of SOX9 protein in the tissues of patients with ovarian carcinoma with non-malignant ovarian tissues. Methods Tissue levels of SOX9 protein were estimated in the study and control groups (60 each group). SOX9 levels were compared between the study vs. control groups and also between high grade and low-grade ovarian cancer. SK-OV3 ovarian adenocarcinoma cell line was used as supportive evidence to prove the presence of SOX9 in malignant ovarian cells. Results Levels of SOX 9 protein (3.9±2.7 ng/mL) were high in tissue of ovarian cancer patients when compared to non-malignant (1.5 ±1.1 ng/mL) ovarian tissues. Higher levels of SOX 9 protein were found in tissues of ovarian cancer patients when compared to non-malignant ovarian tissues. The mean of SOX 9 levels in tissues of high-grade serous carcinoma was 3.5±2.5 ng/mL as compared to 1.0±0.9 ng/mL in low-grade serous carcinoma. Interpretation and conclusions SOX9 appears to be an important player in the molecular tumourigenesis of ovarian cancer, particularly in high grade tumours.

Background and objectives Genomic studies are essential for identifying mutations that may influence key aspects of breast tumours, such as susceptibility, aggressiveness, and response to treatment. There are deficient molecular and genomic data from Indian breast cancer patients. Methods mRNA from primary breast cancer samples were subjected to next-generation transcriptome (mRNA) sequencing on an Illumina platform, in duplicates and triplicates to generate 30-60 M reads/sample. PAM50, and absolute intrinsic molecular subtyping (AIMS) gene expression-based classifiers were used for intrinsic subtyping. Variants were called using, GATK, MuTect2, VarScan2, and VarDict, followed by filtering for somatic and non-synonymous changes. Germline variants were excluded using public databases. ClinVar annotations prioritised pathogenic variants, and the STRING algorithm was used for network analysis. Results A total of 207 RNA-Seq datasets from 97 breast cancer patients were analysed. There was good concordance between the immunohistochemical receptor and AIMS classification for all subtypes, but there was discordance between immunohistochemical and PAM50 subtypes within the ER-positive/HER2-positive subgroup, wherein only 38.5% (n= 5) were classified as HER2-like by gene expression classification. Variant analysis identified 145 high-confidence somatic mutations, with TP53 (n=46, 47%) and PIK3CA (n=33, 34%) being the most frequent. Additional actionable mutations in BRCA1, BRCA2, FGFR2, PTEN, AKT1, and mTOR pathways were identified. At least one actionable mutation was found in 52% of patients. Fusion transcript analysis identified 91 recurrent fusions, including novel partners with ERBB2, MED1, and CDK12, suggesting the possibility of unique molecular events. Interpretation and conclusions This study demonstrates that Indian breast cancer patients exhibit molecular subtypes and actionable mutations comparable to Caucasian cohorts.

The tumor microenvironment (TME) significantly influences cancer progression, metastasis, and therapeutic resistance. Among the diverse cellular constituents of the TME, tumor-associated macrophages (TAMs) are critical players that support tumor growth, facilitate angiogenesis, and suppress anti-tumor immune responses. Metabolic reprogramming of TAMs has emerged as a pivotal mechanism driving their immunosuppressive and pro-tumourigenic functions. This extensive review delves into the intricate metabolic pathways involved in TAM reprogramming, the underlying molecular mechanisms, and the impact of these metabolic alterations on the TME. We also explore potential therapeutic strategies targeting TAM metabolism to reprogram the TME and enhance cancer immunotherapy efficacy.

Gastrointestinal (GI) cancers remain a major global health concern characterized by aggressive progression, poor prognosis, and resistance to traditional treatment modalities. Despite significant advancements, conventional treatments like surgery, chemotherapy, and radiotherapy often cause systemic toxicity, lack tumor specificity, multidrug resistance, and risk of relapse, emphasizing the need for safer and more targeted interventions. In response to these challenges, extensive research has focused on natural compounds for GI cancer treatment, with many phytochemicals demonstrating low toxicity and the ability to modulate multiple cancer-related pathways. Among natural compounds, isorhamnetin, a methylated flavonol and quercetin derivative found in various dietary sources, has emerged as a highly promising anticancer agent. Through modulation of various key oncogenic pathways such as PI3K/Akt, MAPK, NF-κB, and Wnt/β-catenin, isorhamnetin exerts pro-apoptotic, antiproliferative, anti-angiogenic, and anti-metastatic effects in various GI cancers. Isorhamnetin's chemopreventive efficacy is further underscored by its anti-inflammatory and antioxidant properties, which are essential in reducing chronic inflammation and oxidative stress commonly involved in GI tumor development. However, its efficacy and clinical translation remain hindered due to pharmacokinetic constraints such as low water solubility and rapid metabolism. Recent emerging nanotechnological approaches aim to address these challenges by enhancing their bioavailability and targeted delivery. This manuscript emphasizes the anticancer potential of isorhamnetin in GI malignancies, with a particular focus on its molecular mechanisms of action, chemopreventive properties, and recent progress in nanoformulation-based strategies.

Low-grade epilepsy-associated tumors are the second common cause of drug-resistant epilepsy, mostly occurring in young adults. The IDH-wild type tumors ganglioglioma (GG) and dysembryoplastic neuroepithelial tumor (DNET) account for the majority of these tumors. Only DNETs have a specific imaging profile of multilobulated cysts oriented in a ball-like fashion or perpendicular to the cortical surface. GG with a predominant neuronal or glial population are more heterogenous and cannot be clearly separated from pilocytic astrocytomas (PAs), pleomorphic xanthoastrocytomas, angiocentric gliomas, and polymorphous low-grade neuroepithelial tumors of the young, respectively.

Tumor tissue engineering, integrating organoid, microfluidic, and biofabrication technologies, has opened new avenues for cancer research. Leveraging advanced bioengineering and biomaterials, these 3D models capture tumor architecture, cellular heterogeneity, biomechanics, and biochemical characteristics for disease modeling. Despite recognition that tissue organization influences malignancy and drug resistance, clinically oriented 3D approaches are rare, largely due to tumor microenvironment complexity, cellular plasticity, and interpatient heterogeneity. With a primary emphasis on gastrointestinal malignancies, we outline the capabilities and remaining limitations of organoid-based cancer models, including developmentally defined stem cell-derived systems that enable controlled early-stage modeling when premalignant material is scarce. We discuss patient-derived organoids as clinical avatars for therapy response prediction and summarize recent clinical trials that delineate key bottlenecks hindering routine implementation. Finally, we outline how innovations in biomaterial design, biofabrication, and microfluidics, benchmarking against patient data, and artificial intelligence are converging to better reconstruct tumor complexity, improve experimental tractability, and accelerate translation.

Cellular senescence is a stable and irreversible state of proliferative arrest triggered by diverse stressors, inclh3uding DNA damage, oncogenic signaling, oxidative stress, and metabolic imbalance. Once regarded as a culture artifact, senescence is now recognized as a fundamental biological program that governs tissue homeostasis, development, aging, and disease. Based on its origin, senescence can be divided into two principal categories: damage-induced, encompassing replicative, oncogene-induced, and therapy-induced forms, and developmentally programmed, which orchestrates tissue patterning and remodeling during embryogenesis. These processes converge on the activation of p53/p21 and p16/RB tumor suppressor axes, sustained DNA damage response (DDR), and the establishment of the senescence-associated secretory phenotype (SASP). Acute senescence serves beneficial roles in tumor suppression, wound healing, and embryonic morphogenesis by transiently activating SASP-mediated immune clearance. However, persistent senescence becomes detrimental, promoting chronic inflammation, tissue dysfunction, and cancer progression. Within the tumor microenvironment, chronic SASP signaling driven by nuclear factor kB (NF-κB), CCAAT/enhancer-binding protein beta (C/EBPβ), and Signal Transducer and Activator of Transcription 3 (STAT3) fosters epithelial-to-mesenchymal transition (EMT), invasion, and therapy resistance. Therapy-induced senescence (TIS) often leads to polyploidization and the emergence of polyploid giant cancer cells (PGCCs) that can escape arrest, regenerate proliferative progeny, and drive tumor relapses. Thus, senescence represents a biological paradox: a protective, transient process that maintains tissue integrity but, when unresolved, transforms into a driver of aging and malignancy. Understanding the molecular determinants, distinguishing beneficial from pathological senescence is crucial for developing targeted senotherapies.

Obesity is well-documented to increase the risk and worsen the prognosis of various cancers. This review investigates the relationship between obesity and glioma, as a comprehensive analysis has not been conducted. A literature search was conducted across several databases, including ScienceDirect, PubMed, and Google Scholar, from 2004 to 2025, using the keywords: (glioblastoma OR glioma OR GBM) AND (obesity OR "body mass index" OR BMI OR overweight OR adiposity OR "waist circumference") AND (risk OR association OR prevalence OR incidence OR correlation OR etiology). Inclusion criteria focused on studies in English published from 2004 to 2025. From an initial screening of 606 studies, 26 met the criteria.The role of high BMI or waist circumference (WC) as a risk factor remains unclear, with evidence varying by age, gender, and tumor grade. The compound effect of high BMI with high WC is more pronounced in women. Evidence of linearity between BMI and glioma risk is also stronger in women. Notably, low BMI combined with high waist circumference presents a greater risk than high BMI with high waist circumference. Healthy lifestyle factors may influence glioma risk more significantly than BMI. Additionally, elevated BMI in early life (18-21yo) is more consistently associated with increased glioma risk, while height is identified as a common risk factor. Although several studies associate higher BMI with poorer overall survival (OS) and progression-free survival (PFS), some suggest that being overweight may confer a survival advantage compared to normal or underweight individuals. Obesity impacts prognosis more significantly in MGMT-methylated gliomas. Further research is needed to clarify these complex associations.