Cervical cancer is a common cancer among women worldwide. It has been revealed that hypoxia contributes to the progression of cervical cancer. In our study, we discovered that hypoxia indeed promoted the malignant phenotypes of cervical cancer cells by enhancing glycolysis. Loss-of-function experiments showed that hypoxia treatment upregulated the octamer-binding transcriptional factor 4 (OCT4) expression via glycolysis. Through the RNA-sequence and enrichment analyses, we found that hypoxia induced the enrichment of the calcium signaling pathway and upregulation of Calcium Release-Activated Calcium Modulator 3 (ORAI3), which could be abrogated by silencing OCT4. Notably, overexpressing ORAI3 has similar effects on the malignant phenotypes of HeLa and SiHa cells as those of hypoxia. Furthermore, silencing ORAI3 or inactivating calcium signals significantly reversed OCT4-induced malignant progression of cervical cancer both in vitro and in vivo. ChIP and dual-luciferase reporter results confirmed that OCT4 contributed to the transcription of ORAI3. Mechanically, hypoxia upregulated OCT4 expression by facilitating glycolysis, and OCT4 overexpression enhanced the transcription of ORAI3, activating the calcium signaling pathway and ultimately promoting the malignant progression of cervical cancer. Our study reveals novel molecular mechanisms by which hypoxia induces the progression of cervical cancer, providing a new strategy for treating cervical cancer.

Mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) tumors represent a biologically and immunologically distinct subset of solid malignancies. Defective DNA mismatch repair mechanisms in these tumors lead to the accumulation of insertion-deletion mutations, a hypermutated phenotype, and abundant tumor-specific neoantigens. These features drive robust T cell responses, explaining the remarkable sensitivity of dMMR/MSI-H tumors to immune checkpoint inhibitors (ICIs). Emerging evidence from clinical trials across resectable dMMR/MSI-H colorectal, gastric and gastroesophageal junction, and other solid tumors indicate that ICI therapy can induce profound pathological responses, including high rates of pathological complete response. These responses may permit organ preservation and reduce treatment-associated morbidity, offering a compelling alternative to conventional surgery-based approaches. Despite this promise, several challenges remain. Critical areas warranting further investigation include the refinement of patient selection strategies, clarification of the role of surgery in patients achieving a clinical complete response, and the identification of reliable predictive biomarkers for therapeutic response and resistance. In addition, the long-term oncologic outcomes associated with non-operative management remain to be elucidated. This review comprehensively summarizes the biological basis and emerging clinical evidence for immunotherapy in resectable dMMR/MSI-H solid tumors. We discuss current opportunities and ongoing challenges in refining curative-intent strategies, with the aim of improving outcomes and quality of life for patients with these immunologically distinct cancers.

Cancer cells harbor somatic mutations that generate novel amino acid sequences that are absent in the self-proteome. These mutation-derived cancer-specific peptides are defined as "neo-peptides". Neo-peptides eliciting immune responses, i.e. immunogenic neo-peptides, are defined as "neo-epitopes". Given their relevance to cancer immunotherapy, we conducted a meta-analysis to examine how experimental evidence informs our understanding of neo-epitopes. Our study is the largest reported to date. Using the cancer epitope database and analysis resource (CEDAR), we analyzed over 16,000 neo-peptides tested in more than 20,000 T cell assays across 180 studies. We found that validated neo-epitope frequencies varied across cancer types, with the highest rates in skin and lung and the lowest in colorectal cancer. Neo-epitopes were enriched in driver genes such as TP53 and KRAS. However, testing frequency correlated with mutation prevalence, revealing bias toward recurrent mutations. Despite the high sequence similarity among RAS family members, validated neo-epitope overlap was minimal, challenging pan-RAS strategies. Shared neo-epitopes across cancer types are rare, with only 16 validated in more than one cancer type. While most assays involved HLA class I, class II alleles presented a higher proportion of validated neo-epitopes. Specific alleles, including HLA-B*40:01 and HLA-DRB1*11:01, were enriched for neo-epitopes, whereas others, like HLA-A*02:01, were enriched for non-immunogenic neo-peptides. Finally, amino acid substitutions that altered hydrophobicity or charge were more common in neo-epitopes. Together, these findings define key features of neo-epitopes, expose methodological and biological biases in the literature, and highlight opportunities to improve the selection and prioritization of neo-epitopes for cancer immunotherapy.

The MEK-ERK pathway is a key driver of hepatocellular carcinoma (HCC) pathogenesis, and BRAF mutations, particularly BRAFV600E, can contribute to its activation. Although BRAFV600E mutations are rare in human HCC, they do occur, yet their physiologic impact in liver cells, especially when combined with frequent comutations in tumor suppressor genes, remains poorly understood. Moreover, the effect of BRAF inhibitors on HCC progression and metastasis is not well-defined. Therefore, we developed mouse models with hepatocyte-specific BRAFV600E expression and Trp53 or Cdkn2a deletion to assess tumor development, subtypes, and metastatic patterns. We found that BRAFV600E expression caused hepatomegaly, vascular congestion, and ductal reactions, and led to reduced liver function and early mortality. Codeletion of Trp53 or Cdkn2a markedly increased primary liver tumor incidence and enabled sarcomatoid metastasis. While the BRAF inhibitor PLX4720 effectively reduced primary tumors and extended survival, it paradoxically increased sarcomatoid metastases. Mechanistically, PLX4720 and other RAF inhibitors induced TGFβ2 expression which promoted epithelial-to-mesenchymal transition (EMT) and enhanced tumorigenicity. The effects of RAF inhibitors on TGFβ2 expression were validated in BRAFV600E-mutant human melanoma cells. We conclude that BRAFV600E drives diverse primary tumors but only one type of metastasis and that RAF inhibition, while effective against primary tumors, may promote metastasis through TGFβ2-mediated EMT. Although RAF inhibitors remain promising therapies, their unintended role in enhancing metastasis raises concerns that may extend beyond liver cancer to other BRAFV600E-driven malignancies.

Benign and malignant (cancerous) tumors differ markedly in their impact on organismal fitness, yet studies in comparative oncology rarely distinguish between them. Using a Bayesian phylogenetic framework across birds and mammals, we show that while both tumor types increase in prevalence with body mass, only the prevalence of malignant tumors is negatively associated with the rate of body size evolution-suggesting that adaptive mechanisms of cancer defense are associated with rapidly evolving lineages. Additionally, the rate of lineage diversification is positively associated with the prevalence of both tumor types in birds but not mammals, potentially reflecting differences in genome architecture and speciation dynamics. Together, these results highlight distinct macroevolutionary drivers of benign versus malignant tumor prevalence and underscore the value of treating tumor types separately in comparative oncology.

Metabolic pathways are typically dysregulated in cancer to support critical cellular processes. In response to metabolic disturbances, cancer cells preferentially manipulate stress sensors to enhance their adaptability. Sestrin 2 (SESN2), a highly conserved protein induced by various stressors, is implicated in this adaptation. Mutations and alterations of SESN2 are prevalent among cancer patients, suggesting a potential role in tumor progression. However, the functions and regulation of SESN2 in cancer, particularly in virus-induced cancer, remain largely unknown. In this study, we demonstrate that latent infection with Kaposi's sarcoma-associated herpesvirus (KSHV) stabilizes and upregulates SESN2 by inhibiting its proteasomal degradation across multiple cell lines. Notably, KSHV-encoded vCyclin, a homolog of cellular Cyclin D, directly interacts with SESN2 and promotes its stabilization by recruiting the deubiquitinase OTUB1, thereby blocking SESN2 polyubiquitination and proteasomal degradation. Moreover, vCyclin- and OTUB1-mediated stabilization of SESN2 activates AMP-activated protein kinase (AMPK), which supports the survival and growth of KSHV-driven primary effusion lymphoma cells. Importantly, the lysine at residue 74 of vCyclin is crucial for its cytosolic localization, OTUB1 recruitment, and subsequent SESN2 upregulation and AMPK activation. These findings unveil a regulatory mechanism for SESN2 involving vCyclin and OTUB1, positioning them as potential therapeutic targets for diseases associated with AMPK dysregulation.

Thyroid nodules are common, and the majority are of benign nature, however the main clinical aim remains to discriminate malignant ones. Despite that, the actual routine workup for thyroid nodules including hormonal testing, ultrasound scan, scintigraphy, and Fine needle aspiration cytology (FNAC) is still deficient, often necessitating surgical intervention for a conclusive histopathological examination and diagnosis. Therefore, searching for molecular tools that help in differentiating benign and malignant thyroid nodules gains an increasing interest.

Secretory breast carcinoma (SBC) is a rare tumour defined by ETV6-NTRK3 rearrangement, but its clinicopathological spectrum and potential for aggressive behaviour remain incompletely characterised. We retrospectively reviewed 29 SBCs diagnosed between 2014 and 2024, including 28 females and one male aged 12-63 years (median 44). Twenty-eight tumours arose in the breast parenchyma and one in axillary accessory breast tissue. Histologically, microcystic and tubular patterns predominated and carcinoma in situ was common. Most tumours were nuclear grade 1 with rare mitoses (0-1/10 high-power fields, HPF). A single patient with distant metastasis harboured a solid-predominant tumour showing nuclear grade 2-3, brisk mitoses (6/10 HPF), and multifocal necrosis. All tumours demonstrated diffuse S100 and pan-TRK expression. Oestrogen and/or progesterone receptor staining was observed in 16 of 29 cases (2-30% of tumour cells), and all were HER2 negative or low (0-1+). Ki-67 ranged from 3% to 20% (mean 7%). Fluorescence in situ hybridisation (FISH) was positive in 17 of 17 tested tumours (14 ETV6-NTRK3 dual-fusion; 3 NTRK3 break-apart). In the metastatic case, RNA sequencing confirmed canonical ETV6-NTRK3 fusion, while targeted DNA sequencing identified additional variants of uncertain significance (VUS) - RANBP2 p.S1843R, NUP107 p.K382Q, NCOR1 p.A1947V (missense), and PREX2 p.G606G (synonymous). All patients underwent surgery, and 14 received adjuvant chemotherapy. During follow-up ranging from 6 to 135 months (median 76), one patient developed lung metastasis and was alive with disease at 88 months; the remaining 28 patients were alive without recurrence or metastasis. In summary, SBC is typically indolent and characterised by ETV6-NTRK3 rearrangement with diffuse pan-TRK/S100 positivity. A solid-predominant pattern with increased cytological atypia, mitotic activity, and necrosis may indicate aggressive potential. Routine NTRK testing supports diagnosis and may help identify patients who could benefit from TRK-inhibitor therapy in advanced disease.

Less than half of the human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC) patients respond to trastuzumab plus chemotherapy, and the outcomes are unsatisfactory. Understanding the underlying mechanisms remains crucial for identifying patients who are more likely to benefit from treatment.

Non-gestational choriocarcinoma (NGCC) is a rare type of malignant tumor. Primary lesions are typically detected in the ovary and rarely invade the corpus uteri and cervix. NGCC usually has a poor prognosis due to the difficulty in achieving early and accurate diagnoses because of its rarity.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder that is characterized by hormonal imbalances and ovarian dysfunction. Obesity is also a prevalent issue that has been linked to the development of PCOS. The present study aimed to investigate the gene expression of αvβ3 integrin, mucin-1, and E-cadherin in obese and non-obese women with and without PCOS.

Major Facilitator Superfamily Domain-containing 12 (MFSD12) has emerged as a critical transmembrane protein with increasingly recognized roles in various cancers. The complex pathogenesis and therapeutic resistance of liver hepatocellular carcinoma (LIHC) present significant clinical challenges. This study investigates MFSD12's potential involvement in LIHC progression.

CD8+ T cells play a pivotal role in antiviral and antitumor immunity, yet under chronic antigen stimulation, they progressively enter a functionally impaired "exhausted" state, characterized by loss of effector functions, sustained high expression of inhibitory receptors, and a distinct transcriptional and epigenetic landscape. Recent studies have highlighted that epigenetic regulation is central to the initiation and maintenance of CD8+ T cell exhaustion. Exhausted T cells exhibit chromatin landscapes markedly different from those of effector and memory T cells, displaying an "epigenetic locking" that renders their phenotype largely irreversible. Emerging evidence highlights the central role of epigenetic and transcriptional regulation in driving and maintaining CD8+ T cell exhaustion. DNA methylation and histone modifications establish stable repressive chromatin landscapes that suppress effector gene programs. Non-coding RNAs, including microRNAs and long non-coding RNAs, fine-tune exhaustion-associated pathways post-transcriptionally, while RNA epigenetic modifications, such as m6A methylation, regulate transcript stability and translation in exhausted T cells. Transcription factors orchestrate these epigenetic and post-transcriptional networks, reinforcing exhaustion-specific gene expression profiles. Together, these interconnected mechanisms not only define the exhausted phenotype but also contribute to tumor immune evasion and therapeutic resistance. Understanding these processes provides a framework for novel strategies aimed at reversing CD8+ T cell exhaustion and improving the efficacy of cancer immunotherapy. Collectively, elucidating the epigenetic mechanisms underlying CD8+ T cell exhaustion not only deepens our understanding of its molecular basis but also provides new avenues for precision immunotherapy and individualized interventions.

The integration of genomic tests such as the Oncotype DX Breast Recurrence Score® test, into routine clinical practice represents a significant advance in personalized breast cancer care. By supporting more tailored therapeutic decisions, these diagnostics can improve patient outcomes, while reducing risks of undertreatment, overtreatment, and associated side effects. Cost-effectiveness has already been demonstrated in numerous publications. However, for widespread adoption across Europe, four principal challenges must be overcome: regulation, technology assessment, reimbursement, and gaps in real-world evidence. Since May 2022, the European Union In Vitro Diagnostics Regulation (IVDR) has updated requirements for demonstrating clinical utility and analytical and scientific validity, creating new barriers for manufacturers regarding primary evidence generation. Variability in health technology assessment (HTA) frameworks and reimbursement mechanisms across countries further complicates adoption. Demonstrating real-world benefits of these technologies requires robust, representative data collections, yet current clinical trial evidence often underrepresents certain patient populations, raising equity concerns. Whilst the IVDR will help standardize regulatory requirements, challenges remain in harmonizing evidence standards for HTA and reimbursement. This review explores these barriers using the Oncotype DX® test as an exemplar. Evidence was drawn from targeted literature searches and reviews of regulatory, reimbursement, and gray literature relevant to European healthcare systems.

This study contributes to the characterization of human macrophages in normal and pathological conditions such as cancer. We characterized a macrophage population expressing membrane-associated IL-18 (mIL-18) that shows peculiar proteomic, phenotypic, ultrastructural, and functional properties. mIL-18+ macrophages exhibit increased levels of key proteins involved in pathogen recognition, activation, migration, and endocytosis. They also display specialized functions in vesicle and actin filament transport and lipid metabolism, and have typical mitochondrial traits. Importantly, mIL-18+ cells dominate the peritoneal fluid of adult cancer patients and are present in the bone marrow of children with neuroblastoma. They express high levels of TREM2 but display heterogeneous FOLR2 expression, distinguishing distinct cell subsets with possibly different functions. Accordingly, in primary neuroblastomas, transcriptional signatures associated with mIL-18 expression show different prognostic values. Our data show that mIL-18+ macrophages, which are predominant across the tumor microenvironment, exhibit previously undetected heterogeneity, potentially impacting tumor progression in a variable manner.

(Abstracted from Obstet Gynecol 2025;146(2):223-232) Awareness of hereditary gynecologic cancer has been growing over the last few decades, and testing and prevention methods have been decreasing in cost. This means that more people who have gene mutations for these hereditary cancers more often face decisions about risk-reducing bilateral salpingo-oophorectomy (BSO).

Constitutional primary monoallelic promoter methylation of hereditary cancer genes, although rare, may explain early-onset cancers without family history. Also, promoter methylation of a hereditary cancer gene secondary to a genetic alteration in a methylation regulatory region can cause a hereditary cancer syndrome. This study investigates constitutional promoter methylation as mechanism of inactivation of cancer predisposition genes in genetically unsolved familial and/or early-onset colorectal cancer (CRC) patients.

Carboplatin resistance represents a critical therapeutic challenge in non-small cell lung cancer (NSCLC) treatment. Although KHSRP has been implicated in lung cancer progression, its molecular mechanisms and impacts on chemotherapy sensitivity remain elusive. Notably, KHSRP has the capacity to activate the transcription of HMGB1, an oncogene known to influence chemotherapy sensitivity. However, it remains to be determined whether KHSRP affects chemotherapy response in NSCLC via HMGB1.

Triple negative breast cancer (TNBC) is an aggressive subtype with limitations in therapy. Although cyclin dependent kinase inhibitors (CDKi) have been proven in breast cancer, challenges remain in TNBC. Successful inhibition of CDK4/6 relies on intact Rb tumor suppressor (encoded by tumor suppressor gene RB1). However, in addition to gene mutation or deletion, RB1, as an imprinted gene, also has a mechanism of inactivation due to loss of imprinting (LOI). This study aimed to ascertain the imprinting status of RB1 in TNBC.

HPV-negative (-) head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous cancer characterized by high mutational burden, an immunosuppressive microenvironment, and poor response to standard therapies. These features highlight the urgent need for novel and more effective treatment strategies.