Dendritic cells (DCs) play a crucial role in the coordination of immune responses and have emerged as a potential target for cancer immunotherapy. However, existing DC-based immunotherapies face several clinical challenges, including suboptimal manipulation strategies, poor cross-presentation, and impaired migration. Besides, the complex tumor milieu drives DCs towards a tolerogenic state, leading to immune evasion and cancer progression. Hence, innovative engineering strategies emerging from a thorough understanding of the genetic and molecular aspects of the factors driving DCs to an immune-compromised status will benefit cancer immunotherapy. Taking advantage of the multiplexing potential of gene editing methods such as CRISPR/Cas9 and viral vectors will ensure multiple genome modifications in DCs that can result in higher migration, cross-presentation, and immune-activating cytokine production in a single manipulation step. Such precise DC modifications with high accuracy require the involvement of nanocarrier formulations with high surface functionalization and targeting potential. In this regard, our review provides a comprehensive summary of critical tumor-induced dysfunctions in DCs and promising genome engineering strategies, highlighting nanocarrier-based approaches to mitigate these challenges.

Ferroptosis is an iron-dependent form of programmed cell death driven by the accumulation of lipid peroxides. KHSRP, an RNA-binding protein, is known to orchestrate diverse cellular processes, including cell differentiation, proliferation, and lipid metabolism. However, its potential role in modulating ferroptosis in cancer remains unclear. In this study, we found that elevated KHSRP expression was associated with poor prognosis in colorectal cancer (CRC) patients. Knockdown of KHSRP significantly elevated lipid peroxidation, increased malondialdehyde (MDA) accumulation, and reduced glutathione (GSH) levels, ultimately triggering ferroptosis in CRC cells. Mechanistically, we discovered that KHSRP interacts with the splicing factor hnRNPM, which directly binds to GPX4 mRNA. Critically, hnRNPM overexpression effectively rescued the decrease in GPX4 expression and the ferroptotic phenotype induced by KHSRP knockdown. These results suggest that the KHSRP-hnRNPM complex binds to GPX4 mRNA and acts as a key regulator of its post-transcriptional fate to sustain GPX4 expression. Overall, our results uncover a novel regulatory mechanism whereby high KHSRP expression protects CRC cells from ferroptosis. Targeting the KHSRP-hnRNPM-GPX4 axis to overcome ferroptosis resistance represents a promising therapeutic strategy for CRC.

Melanoma is an aggressive malignancy with one of the highest mortality rates among skin cancers. Radiotherapy is a common treatment modality, but radioresistance remains a significant challenge. The stimulator of interferon genes (STING) pathway has been implicated in antitumor immunity and cancer treatment, yet its role in melanoma radiosensitivity is poorly understood.

PRDM15, a member of the PRDM family, is critically involved in embryonic development, cell differentiation, and tumorigenesis. However, its specific regulatory mechanisms in tumorigenesis remain poorly understood. This study demonstrates that PRDM15 is significantly upregulated in colorectal cancer (CRC) tissues and positively correlates with advanced pathological staging. Knockdown of PRDM15 inhibits p53-dependent cell proliferation by arresting cell cycle progression and promoting apoptosis, thereby suppressing colorectal carcinogenesis both in vitro and in vivo. Furthermore, PRDM15 depletion enhances the sensitivity of HCT116 cells to the chemotherapeutic agent 5-Fluorouracil (5-FU). Mechanistically, PRDM15 functions as a novel negative regulator of p53, exerting its oncogenic effects by transcriptionally downregulating USP10, which in turn destabilizes p53. These findings underscore the critical role of the PRDM15-USP10-p53 axis in CRC progression, offering new insights into the molecular mechanisms driving CRC and identifying potential therapeutic targets for intervention.

Nectin-4-MMAE is an innovative antibody-drug conjugate (ADC) that combines a Nectin-4-targeting monoclonal antibody with monomethyl auristatin E (MMAE), a potent microtubule inhibitor, demonstrating substantial therapeutic promise. While previous research has primarily focused on Nectin-4-targeted therapies in urothelial carcinoma, their potential efficacy in gastric cancer (GC) has yet to be thoroughly investigated. To bridge this knowledge gap, this study seeks to investigate the therapeutic effects of Nectin-4-MMAE in GC and examine the mechanistic role of autophagy in the treatment of Nectin-4-positive gastric cancer. Apoptosis and autophagy induced by NECTIN-4-MMAE were validated using 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) assay, flow cytometry (FCM), transmission electron microscopy (TEM), confocal microscopy, and Western blotting (WB). Gene enrichment analysis was performed based on RNA Sequencing (RNA-seq) data. Finally, the antitumor effects of NECTIN-4-MMAE, with or without the autophagy inhibitor, were confirmed in a mouse xenograft model. Our findings indicate that Nectin-4-MMAE induces both apoptotic cell and protective autophagy. Notably, the combination of Nectin-4-MMAE with autophagy inhibitors demonstrated a markedly stronger inhibitory effect on gastric cancer cells than Nectin-4-MMAE alone. These results suggest a viable therapeutic approach for treating Nectin-4-positive gastric cancer through the combinatorial use of Nectin-4-MMAE with autophagy inhibitors.

Patients who initially respond to immune checkpoint inhibitors (ICIs) often relapse. Here, we studied how disease-progressive (DP) clinical melanomas evolve genomically to acquire ICI resistance. Compared to patient-matched pretreatment tumors, DP tumors recurrently amplified and/or deleted anti-apoptotic and/or pro-apoptotic genes, respectively. By chronic exposure to killer T cells or ICI therapy, we derived acquired-resistant (AR) human melanoma cell lines and murine melanoma tumors that recapitulate co-occurrent copy-number variants (CNVs) of apoptotic genes observed in DP melanomas. AR and DP subclones expanded shared, private, and, in some subclones, preexistent driver CNVs. Compared to isogenic parental cells, AR melanoma cells attenuated apoptotic priming but, with overexpression of deleted pro-apoptotic genes, recovered mitochondrial priming and sensitivity to killer T cells or ICIs. In mice, pharmacologically reducing the apoptotic threshold of ICI persisters prevented relapses. Thus, CNVs can drive the evolution of resistance to ICIs in melanoma, with tumor cell-intrinsic apoptotic threshold representing a target to curtail persister evolution.

Thyroid cancer is the most prevalent endocrine malignancy. Distinct genetic alterations drive the development and progression of thyroid tumors of follicular cells with remarkable genotype-phenotype correlation. In most tumors of follicular cell origin, the primary molecular events are RAS or RAS-like (follicular-patterned tumors) and BRAF p.V600E or BRAF V600E-like (conventional papillary carcinomas) alterations. Progression of thyroid tumors to advanced and less-differentiated carcinomas requires additional oncogenic alterations, including TP53 and TERT promoter mutation, and aberrant PI3K-PTEN-AKT signaling. Understanding the genetic landscape of thyroid carcinoma of follicular cells is essential to optimize clinical management and to identify molecular targets to treat cases with aggressive disease refractory to standard radioactive iodine therapy. What follows is a comprehensive and updated outline of the main somatic genetic and molecular alterations in thyroid carcinoma of follicular cells.

Immune checkpoint therapy (ICT) has revolutionized the treatment of gastric cancer (GC), but only a small part of patients benefits from it, highlighting the urgency of developing models for precise immunotherapy response prediction of GC patients. However, the development of such models is hindered by the limited availability of ICT-related data. This study aimed to develop an accurate prediction model for immunotherapy response in GC patients using data augmentation and active learning techniques.

Wilms' tumor (WT) and rhabdoid tumor (RT) are the predominant renal neoplasms in pediatric patients, and their metastatic potential significantly impacts the prognosis of affected children. However, limited research has been conducted on elucidating the underlying molecular mechanisms driving metastasis in these tumors, resulting in a dearth of well-defined molecular targets. Based on the clinical staging information available in the TARGET database for WT and RT, we investigated the differential gene expression profiles and associated molecular pathways implicated in metastasis. Interestingly, our analysis revealed that WT and RT tumor metastases shared a highly expressed gene IMPA2, which was associated with poor prognosis. Additionally, experimental validation confirmed that IMPA2 exerted regulatory effects on the Wnt signaling pathway as well as N-cadherin and E-cadherin levels, thereby influencing the migratory and invasive capabilities of G401 cells. Moreover, gene profiles and molecular pathways associated with IMPA2 expression were comprehensively analyzed, transcription factors potentially regulating IMPA2 were identified, and correlations with immune-related genes were determined. Regarding therapy, we identified small molecule drugs that affected IMPA2 expression and utilized molecular docking to predict their direct binding to the IMPA2 protein. These findings have provided biomarkers and therapeutic targets for the metastatic WT and RT, while the investigated targeted drugs hold promise as novel therapeutic strategies to enhance the prognosis of affected children.

Dysregulation of RNA binding proteins (RBPs) is a hallmark in cancerous cells. In acute myeloid leukaemia (AML) RBPs are key regulators of tumour proliferation. While classical RBPs have defined RNA binding domains, RNA recognition and function in AML by non-canonical RBPs (ncRBPs) remain unclear. Given the inherent complexity of targeting AML broadly, our goal was to uncover potential ncRBP candidates critical for AML survival using a CRISPR/Cas-based screening. We identified the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as a pro-proliferative factor in AML cells. Based on cross-linking and immunoprecipitation (CLIP), we are defining the global targetome, detecting novel RNA targets mainly located within 5'UTRs, including GAPDH, RPL13a, and PKM. The knockdown of GAPDH unveiled genetic pathways related to ribosome biogenesis, translation initiation, and regulation. Moreover, we demonstrated a stabilizing effect through GAPDH binding to target transcripts including its own mRNA. The present findings provide new insights on the RNA functions and characteristics of GAPDH in AML.

Colorectal cancer (CRC) is a common gastrointestinal tumor with a high incidence worldwide. L1 cell adhesion molecule (L1CAM) is highly expressed in CRC tissues and can promote tumor growth and metastasis. Autophagy regulates oncogenesis and tumor progression through context-dependent mechanisms and is regulated by multiple signaling pathways, including the p38 MAPK signaling pathway.

Spermine synthase (Sms), a key enzyme in polyamine biosynthesis, catalyzes the conversion of spermidine to spermine using decarboxylated S-adenosylmethionine (dcAdoMet) as an aminopropyl donor. Although Sms is well-characterized in eukaryotes, it is relatively rare in bacteria, where spermine in some species is probably produced by non-specific aminopropyltransferases. In humans, SMS mutations cause Snyder-Robinson syndrome (SRS), an X-linked disorder characterized by intellectual disability, osteoporosis, and neurological dysfunction due to disrupted polyamine homeostasis. Structural studies reveal that Sms functions as a dimer, with its N-terminal domain essential for enzymatic activity. Loss of Sms leads to spermine deficiency, elevated spermidine levels, and metabolic imbalances, contributing to SRS pathology. Therapeutic strategies under investigation include rebalancing spermidine/spermine ratio, polyamine biosynthesis inhibitors (e.g., DFMO), antioxidants and gene therapy using AAV vectors. Conversely, in multiple cancer types, Sms overexpression promotes tumor progression by altering polyamine metabolism, activating oncogenic pathways (e.g., AKT, mTOR), and facilitating immune evasion. Elevated Sms expression correlates with poor prognosis in colorectal, pancreatic, hepatocellular, and head and neck cancers, highlighting its potential as a therapeutic target. However, spermine's role is context-dependent, exhibiting both pro-tumorigenic and cytotoxic effects. While inhibition of Sms may suppress cancer growth, its deficiency in SRS underscores the delicate balance required in polyamine regulation. Insights from SRS and cancer studies highlight Sms as a critical enzyme in cellular homeostasis, with therapeutic implications for both degenerative and proliferative diseases. Further research is needed to elucidate its complex role and optimize targeted interventions.

As a common endocrinopathy of reproductive-aged women, polycystic ovary syndrome (PCOS) is characterized by ovarian hyperandrogenism, insulin resistance, and preferential abdominal fat accumulation. These characteristics in normal-weight women with PCOS are accompanied by subcutaneous abdominal adipose stem cells that intrinsically exaggerate lipid accumulation during adipocyte development in vitro in combination with an increased amount of highly lipolytic visceral fat. PCOS-related adipose characteristics are intimately linked with hyperandrogenism through genetic inheritance and epigenetic events programmed during prenatal and postnatal life. Accordingly, evolutionary theory submits that such events in PCOS may have ancestral origins, providing survival advantages in 3 contexts: (1) food scarcity with risk of starvation; (2) infectious disease risks, alleviated by visceral and omental fat; and (3) benefits from increased muscularity. But such adaptations also involve costs, given that PCOS-related traits also tend to reduce reproduction, due to oligo-anovulation. This review examines the evolutionary origins of PCOS risk as a syndrome potentiated by environmental mismatches (especially contemporary obesity and low physical activity), combined with adaptive physiological systems governed by trade-offs between survival and reproduction. This hypothesis is supported by a plethora of recent studies on physiological and behavioral differences between subsistence-level and modern Westernized populations, and by analyses of survival-reproduction trade-offs in nonhuman mammals. Studies of PCOS models using prenatally testosterone-treated and naturally hyperandrogenic animal models provide crucial insights for understanding how today's illnesses likely emerged from ancient developmental-metabolic strategies, and how knowledge about the evolutionary past can help guide current research and the development of more effective therapies.

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide, with drug resistance being a major challenge in limiting the available treatment options. This review focuses on the signaling pathways (Hedgehog, Hippo, Notch, Wnt/β-catenin, PI3K/Akt, and MAPK/ERK pathways) that are implicated in the development of drug resistance mechanisms in CRC, such as DNA repair systems, tumor microenvironments, autophagy, metabolic reprogramming, evasion of apoptosis, and efflux pumps. Furthermore, recent advancements in targeted and combinatorial diagnostic-therapeutic approaches are highlighted. This review delineates the significance of signaling cascades and their clinical relevance, offering novel perspectives on the formulation of therapeutic strategies to mitigate drug resistance. In light of the increasing prevalence of drug-resistant CRC and the lack of effective solutions, it addresses the persistent demand for improved therapeutic modalities and provides a comprehensive framework for forthcoming research in this domain.

Prolonged use of conventional chemotherapy has led to adverse side effects and drug resistance, leading to therapeutic failure in colon cancer patients. An alternative therapy involving natural products with least toxicity can show promising results in cancer therapeutics. A bioactive alkaloid Piperlongumine (PIP), found in our culinary spice, exhibits potential pharmacological relevance, especially regarding its anticancer effects. This study is an original research work examining the anticancer efficacy of PIP and its related molecular mechanisms in human colon cancer cells. The results revealed that PIP induces selective cytotoxicity against colon cancer cells while inhibiting proliferation, migration and invasion. PIP also builds up reactive oxygen species (ROS) that increase the oxidative stress of the cells leading to disruption of the mitochondrial membrane and loss of mitochondrial membrane potential. In addition, PIP induces cell cycle arrest at the G2/M phase of the cell cycle and impedes the epithelial-to-mesenchymal transition in colon cancer cells. Further, PIP-mediated elevated intracellular ROS induces DNA damage and activates the caspase-dependent apoptotic pathway in colon cancer cells. PIP also reports an anti-tumorigenic effect on the multicellular tumor spheroids of colon cancer cells. Collectively, these findings validate that PIP shows promising anticancer potential towards colon cancer cells and is a potential candidate for use in combination with existing anticancer drugs.

Neoadjuvant therapy plays an important role in the treatment of glioblastoma (GBM), but a considerable proportion of patients remain unresponsive to the combination of immune checkpoint blockade (ICB) and antiangiogenic therapy. Understanding the mechanisms underlying resistance to this treatment and developing novel therapeutic strategies are crucial.

Embryonic Transcription Factors (TFs) are often reactivated in cancer, driving developmental gene programs that support phenotypic plasticity. Metabolic adaptation fuels this plasticity by supplying energy and molecular building blocks for growth. RUNX2, the master regulator of bone morphogenesis, is ectopically expressed in epithelial cancer, promoting metastasis through trans-differentiation processes like Epithelial-to-Mesenchymal Transition (EMT) and osteomimicry. By combining omics data with functional validation, we demonstrated that RUNX2 drives cancer cell metabolic rewiring by repressing mitochondrial respiration while promoting anabolic processes. We showed that RUNX2 upregulates key genes of lipid biosynthesis by regulating and cooperating with SREBP1. In vivo expression analysis in thyroid and breast cancer patients confirmed that lipid metabolism and SREBF1 expression are associated with increased metastatic potential and clinical aggressiveness. These findings emphasize the RUNX2 role in cancer plasticity and indicate metabolic adaptation as an integral part of the trans-differentiation program induced by this TF during cancer progression.

This study aimed to identify reliable prognostic biomarkers and novel therapeutic targets for Luminal A subtype breast cancer, a prevalent subtype with unmet needs in overcoming endocrine resistance. Given the rising global incidence of breast cancer, high recurrence/drug resistance rates in Luminal A patients, and limited research on ferroptosis in this subtype, we analyzed 421 Luminal A subtype breast cancer samples and 113 adjacent normal tissues from The Cancer Genome Atlas (TCGA) database. Differential expression analysis (log₂|fold change|>1, p < 0.05) and univariate Cox regression for overall survival (OS) identified 12 ferroptosis-related differentially expressed genes (DEGs) with prognostic value. Using Lasso-Cox regression (10-fold cross-validation to avoid overfitting), we further optimized these into a 9-gene prognostic model. Univariate and multivariate Cox regression confirmed the model-derived risk score as an independent prognostic factor for OS (HR = 3.896, 95% CI = 2.195-6.916, p < 0.001) in TCGA. External validation in the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohort (584 Luminal A samples) demonstrated consistent prognostic performance (log-rank p < 0.001), confirming the model's robustness. Functional enrichment analysis showed these genes were enriched in ferroptosis-related pathways, including "lipid biosynthetic process"(Gene Ontology) and "FoxO signaling pathway" (Kyoto Encyclopedia of Genes and Genomes). Single-sample gene set enrichment analysis revealed high-risk groups had increased infiltration of immunosuppressive cells (mast cells, neutrophils, regulatory T cells) and elevated type II interferon response, while low-risk groups had higher type I interferon response. Spearman's correlation analysis identified ENPP2 as a key mediator of immune escape, with a strong positive correlation with PD-1 (r = 0.46, p = 8.7e-24). This 9-gene ferroptosis-related model provides a robust tool for OS prediction in Luminal A subtype breast cancer and highlights ENPP2 as a potential target for combining ferroptosis inducers with immune checkpoint inhibitors-offering a novel strategy for endocrine-resistant patients.

Oral squamous cell carcinoma (OSCC) remains a major global health burden, often diagnosed at advanced stages, with limited survival improvement. Epigenetic dysregulation, particularly promoter hypermethylation, plays a significant role in OSCC pathogenesis. Previous study by Demokan et al. identified Gamma-Aminobutyric Acid Receptor Beta-2 (GABRB2) as a candidate gene subject to methylation-dependent transcriptional silencing. This study aimed to evaluate the methylation and expression profiles of GABRB2 in OSCC and to explore its potential as a diagnostic biomarker.

Ovarian cancer is the eighth most common malignancy among women worldwide. Despite advances in treatment, chemoresistance and associated morbidity remain significant challenges. This study aims to elucidate the role of acetate-dependent acetyl-CoA synthetase 2 (ACSS2) in ovarian cancer progression under hypoxic conditions, identifying its potential as a therapeutic target.