HPV is the central player in this story. Persistent infection with high-risk HPV types is the necessary, though not sufficient, condition for most cervical cancers, and the virus has also been implicated in other gynecological malignancies. Yet infection alone rarely causes cancer. Most women clear the virus within a year or two, and only a minority develop persistent infections that progress through cervical intraepithelial neoplasia to invasive carcinoma. This incomplete penetrance has long suggested that cofactors must determine who progresses and who does not. Smoking, immunosuppression and hormonal factors have all been studied, but the review argues that the microbial communities inhabiting the cervicovaginal environment and the gut may be among the most important and most modifiable of these cofactors.

The vaginal microbiota of reproductive-age women is dominated in most cases by Lactobacillus species, particularly Lactobacillus crispatus, which maintain a low pH environment through the production of lactic acid. This acidic milieu inhibits the growth of pathogens and appears to protect against viral acquisition. Researchers classify vaginal communities into community-state types, and the Lactobacillus-poor types, characterized by a diverse array of anaerobic bacteria such as Gardnerella, Prevotella, Atopobium and Sneathia, are collectively described as vaginal dysbiosis or bacterial vaginosis. Multiple systematic reviews and meta-analyses cited in the review, including work by Brusselaers and colleagues and Norenhag and colleagues, converge on the finding that this dysbiotic state is associated with increased odds of HPV infection, reduced clearance of the virus and higher rates of cervical precancerous lesions.

The mechanistic explanations are increasingly detailed. A diverse, Lactobacillus-depleted vaginal microbiota produces enzymes such as sialidase that degrade the protective cervical mucus barrier, potentially exposing epithelial cells to viral particles. Dysbiotic communities also trigger chronic inflammation, activating pattern recognition receptors such as Toll-like receptors on epithelial and immune cells and driving signaling through the MyD88, TRAF6 and NF-κB pathways. The resulting production of pro-inflammatory cytokines, including tumor necrosis factor-alpha and various interleukins, creates a microenvironment rich in reactive oxygen species, which can damage DNA and promote the genomic instability on which HPV’s oncogenic proteins capitalize. Recent work highlighted in the review suggests that Prevotella, a hub organism in dysbiotic cervicovaginal communities, may promote persistent HPV infection and cervical lesions through host NF-κB signaling, linking a specific bacterial genus to a specific oncogenic pathway.

HPV itself, once established, rewires the local immune landscape in ways that favor its own persistence and further microbial disruption. The virus’s E6 and E7 oncoproteins degrade the p53 and retinoblastoma tumor suppressor pathways, driving cell-cycle entry, but they also interfere with innate antiviral responses. Langerhans cells, the dendritic cell subset patrolling the cervical epithelium, are impaired in their ability to present antigen and activate cytotoxic T lymphocytes during persistent infection. The review describes how this immunosuppressive shift alters the commensal population itself, allowing anaerobic organisms to flourish, which in turn sustains inflammation and further impairs viral clearance. The result is a self-reinforcing loop between dysbiosis and viral persistence that can push lesions toward malignancy.

Perhaps the most intriguing dimension of the review is the gut-vaginal axis. The gut microbiota is the body’s largest immune-training organ, and its metabolites, particularly the short-chain fatty acids produced by fiber-fermenting bacteria such as Bifidobacterium and butyrate-producing colon bacteria, circulate systemically and modulate immune tone far beyond the intestinal wall. Short-chain fatty acids signal through receptors such as FFAR2 and influence T-cell differentiation, regulatory immune responses and epithelial integrity. Studies of the estrogen-gut microbiome axis add another layer, showing that gut bacteria regulate circulating estrogen levels, which in turn affect the vaginal epithelium and its susceptibility to infection. Rectal colonization by Lactobacillus species has even been associated with decreased risk of bacterial vaginosis, suggesting that gut organisms can seed or support protective communities in the genital tract.

Beyond cervical cancer, the review surveys evidence linking microbial communities to endometrial and ovarian malignancies. The once-sterile uterus is now known to harbor a distinct microbiome, and studies such as those by Walther-António and colleagues have found that postmenopausal status shapes the composition of the endometrial cancer microbiome, with dysbiotic communities correlating with inflammatory cytokines in endometrial tumors. Organisms such as Atopobium vaginae and Porphyromonas somerae induce pro-inflammatory cytokine expression in endometrial cells, and vaginal detection of Porphyromonas somerae has been reported as indicative of endometrial cancer diagnosis. In ovarian cancer, a case-control study published in Lancet Oncology by Nené and colleagues associated specific cervicovaginal microbiome profiles with BRCA1 mutation carriers at elevated ovarian cancer risk, while prior Chlamydia trachomatis infection, another microbial insult, has been linked to ovarian cancer risk in large independent cohorts.

The review also acknowledges the technical revolution that made this field possible. Culture-independent methods such as 16S rRNA gene sequencing and next-generation sequencing revealed the true diversity of the vaginal and gut ecosystems, while multi-omics approaches that integrate microbiome, metabolome and transcriptome data are now identifying the most powerful predictors of the cervicovaginal microenvironment. One such study found the metabolome to be the top predictor, underscoring that bacterial metabolites, not merely bacterial identities, may drive the cancer-relevant biology. Systems analyses of the HPV-microbiome-biofilm triad represent the next frontier, modeling how these three elements interact dynamically rather than in isolation.

The translational implications are significant. If dysbiosis genuinely promotes HPV persistence and progression, then microbiome-targeted interventions, from probiotic Lactobacillus supplementation to dietary strategies that boost short-chain fatty acid production, could complement vaccination and screening programs. HPV vaccination remains the most powerful preventive tool, and interestingly, recent studies of vaccinated young women suggest the cervicovaginal microbiome still influences breakthrough infection, indicating that microbial factors operate even in the vaccine era. Screening programs could conceivably incorporate microbiome or metabolite markers to stratify women with HPV infections into higher- and lower-risk groups, sparing low-risk patients unnecessary procedures while intensifying surveillance for those with dysbiotic profiles.

The authors are careful to note the limits of the current evidence. Most studies are cross-sectional, capturing microbiome and HPV status at a single time point, which makes it difficult to distinguish cause from consequence; dysbiosis may predispose to persistent infection, or persistent infection may simply create the conditions for dysbiosis. Longitudinal cohorts tracking temporal dynamics of the vaginal microbiota, such as the work of Gajer and Brotman, have begun to address this, showing that instability of the community itself correlates with HPV detection, but mechanistic proof in model systems remains incomplete. The review’s synthesis nonetheless makes a compelling case that the oncobiome, the collective microbial contribution to cancer, is no mirage in gynecological oncology. Understanding how the trillions of microbes in the gut and vagina negotiate with HPV may ultimately open new avenues for preventing one of the most common cancers affecting women worldwide.

Subject of Research: Interaction between gut and vaginal microbiota, HPV infection and gynecological cancer development

Article Title: Oncobiome relation with HPV and Gynecological cancer

Article References: Soleimanpour, S., & Yaghoubi, A. (2026). Oncobiome relation with HPV and Gynecological cancer. Molecular Biology Reports, 53(1), Article 1681. https://doi.org/10.1007/s11033-026-12856-x

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12856-x

Keywords: oncobiome, HPV, microbiome, dysbiosis, cervical cancer, gynecological cancer, vaginal microbiota, gut microbiota, short-chain fatty acids, endometrial cancer, ovarian cancer, NF-κB

The rationale for the study rests on a well-documented clinical observation. A high prevalence of concurrent PIK3CA and CTNNB1 mutations has been reported among patients with endometrial cancer, yet the functional relationship between the two pathways these genes control has remained murky. PIK3CA drives the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) cascade, a growth-promoting network that has long attracted drug developers. CTNNB1, which encodes β-catenin itself, feeds into the Wnt pathway, a transcriptional program implicated in development and, when dysregulated, in numerous cancers. Whether these two axes cooperate to fuel tumor growth, or whether one could be exploited therapeutically against the other, was an open question.

To answer it, the team assembled a panel of eleven endometrial cancer cell lines and tested three mechanistically distinct inhibitors: ICG-001, which blocks the interaction between β-catenin and its transcriptional co-activator CBP; ipatasertib, an AKT inhibitor; and rapamycin, a classic mTOR inhibitor. The results were strikingly asymmetric. ICG-001, but not the PI3K/AKT/mTOR pathway inhibitors, exhibited potent antiproliferative activity specifically in the cells harboring both CTNNB1 and PIK3CA mutations. In other words, the very pathway combination that had seemed like an obvious target for dual blockade turned out to be most vulnerable to a single intervention on the Wnt side.

Transcriptomic profiling helped explain why. When the double-mutant cells were treated with ICG-001, a series of canonical β-catenin target genes were downregulated, confirming that the drug was doing what it was designed to do at the transcriptional level. But the more revealing finding was what appeared in their place: signature genes related to proteotoxic stress and proteostasis disruption were significantly enriched. Proteostasis, the cellular system that governs the synthesis, folding, and disposal of proteins, is a delicate balance. Its collapse is a recognized form of lethal stress in cancer cells, and the gene expression data suggested that ICG-001 was pushing the double-mutant cells precisely in that direction.

The mechanistic follow-up experiments painted a vivid picture of a cell in crisis. ICG-001 treatment induced de novo protein synthesis, meaning the cells began churning out new proteins at an accelerated rate. At the same time, the researchers observed autophagosome formation, detectable as accumulation of the lipidated form of the protein LC3B (LC3B-II), a hallmark of the cell’s attempt to digest and recycle its own contents. Endoplasmic reticulum expansion, another sign of protein-folding overload, was evident, along with the accumulation of ubiquitinated proteins, the molecular equivalent of garbage piling up faster than the cell’s disposal machinery can clear it. Together, these changes indicate severe proteostasis collapse, a state in which the cell’s protein economy fails catastrophically.

What makes this mechanism particularly compelling is the selectivity. The double-mutant cells appear to be running their protein production machinery close to capacity, perhaps because the combined PIK3CA and CTNNB1 mutations impose unusual demands on translation and folding. When ICG-001 disrupts β-catenin/CBP-dependent transcription, the resulting imbalance between protein synthesis and protein quality control becomes lethal specifically for cells with this genetic background, while sparing cells that lack the double mutation. This kind of synthetic vulnerability, where a drug exploits a weakness created by a specific combination of mutations, is the holy grail of precision oncology, because it promises efficacy with a built-in therapeutic window.

The in vitro findings translated into animal models. Daily administration of ICG-001 demonstrated robust antitumor efficacy in xenograft models of CTNNB1/PIK3CA double-mutant endometrial cancer, meaning tumors grown from the double-mutant cells in mice shrank or stopped growing under treatment. Critically, examination of the xenograft tissues revealed marked ubiquitin accumulation, mirroring the proteostasis collapse seen in cultured cells and confirming that the same mechanism operates in living tumors. This consistency between cell culture and animal data strengthens the case that the observed vulnerability is not an artifact of the laboratory dish but a genuine biological dependency of these tumors.

The study also carries a cautionary message for the alternative strategy. Inhibitors of the PI3K/AKT/mTOR pathway have been extensively developed and tested across many tumor types, with mixed results, and the finding that ipatasertib and rapamycin failed to show preferential activity against the double-mutant endometrial cancer cells suggests that simply attacking the PIK3CA-driven arm of the network may not be the right approach for this subset. The interplay between the two pathways, whatever its details, does not make the PI3K axis the Achilles’ heel. Instead, the data redirect attention toward β-catenin/CBP inhibition as the more productive point of attack.

For patients, the implications are significant but tempered by the usual caveats of preclinical research. ICG-001 is an experimental tool compound, and the path from xenograft efficacy to an approved medicine involves medicinal chemistry optimization, safety profiling, and clinical trials in appropriately selected patients. The study nonetheless establishes a clear biomarker strategy: tumors carrying both PIK3CA and CTNNB1 mutations, identifiable through routine genomic sequencing, would be the candidate population for β-catenin-targeted therapy. Given the high prevalence of this double-mutation pattern in endometrial cancer, the addressable patient group could be substantial, offering hope in a disease where advanced-stage options are currently limited largely to chemotherapy, hormone therapy, and, more recently, immunotherapy for a subset of tumors.

The work also adds to a growing appreciation of proteostasis as a therapeutic target in cancer. Drugs that overload the protein-folding and degradation machinery, such as proteasome inhibitors in multiple myeloma, have already proven that stressing this system can be clinically effective. The present study suggests that transcriptional modulation of β-catenin can trigger a similar collapse in a genetically defined solid tumor, extending the concept into gynecologic oncology. As the authors and their collaborators at the National Cancer Center and the University of Tokyo note, these preclinical findings collectively highlight the vulnerability of PIK3CA/CTNNB1 double-mutant endometrial cancers to β-catenin inhibition and establish β-catenin/CBP inhibitors as a promising targeted therapeutic strategy for this specific genetic subset. Clinical validation will take years, but the study provides the mechanistic foundation and the biomarker logic needed to begin that journey.

Subject of Research: Therapeutic potential of β-catenin inhibition in PIK3CA/CTNNB1 double-mutant endometrial cancer

Article Title: Potential of β-catenin inhibitors as a novel therapeutic strategy for PIK3CA/CTNNB1 double-mutant endometrial cancer

Article References: Nakao, T., Kamata, R., Saito, H., Yamamoto, G., Morita, T. Y., Kinoshita, K., Takahashi, Y., Mashima, C., Yamauchi, T., Sakae, Y., Kamii, M., Nakai, K., Hakozaki, Y., Nakajima, H., Harano, K., Naito, Y., Mukohara, T., & Ohashi, A. (2026). Potential of β-catenin inhibitors as a novel therapeutic strategy for PIK3CA/CTNNB1 double-mutant endometrial cancer. Cell Death Discovery. https://doi.org/10.1038/s41420-026-03321-6

Image Credits: AI Generated

DOI: 10.1038/s41420-026-03321-6

Keywords: endometrial cancer, β-catenin, CTNNB1, PIK3CA, Wnt signaling, ICG-001, proteostasis, targeted therapy, xenograft models, PI3K/AKT/mTOR, proteotoxic stress, precision oncology

The stakes are high because the therapeutic landscape has shifted with remarkable speed. Immune checkpoint inhibitors entered first-line systemic treatment for unresectable stage III–IV or recurrent endometrial cancer on the strength of the RUBY and NRG-GY018 trials, which combined drugs such as dostarlimab and pembrolizumab with standard chemotherapy. More recently, the KEYNOTE-B21 trial pushed immunotherapy even earlier, testing pembrolizumab alongside adjuvant chemotherapy, with or without radiotherapy, in patients with completely resected high-risk disease. Across these studies, checkpoint inhibition has shown its most consistent activity precisely in the dMMR/MSI-H subgroup, whose tumors carry a high mutational burden and are therefore more visible to the immune system. The 2025 ESGO-ESTRO-ESP guidelines responded by recommending that patients with FIGO stage IIIm–IVAm dMMR endometrial carcinoma be considered for adjuvant chemotherapy combined with an immune checkpoint inhibitor, with or without external-beam radiotherapy.

It is that final clause—”with or without EBRT”—that worries the authors. They caution that a superficial reading of the guideline wording could lead clinicians to the unintended conclusion that radiotherapy can be omitted in dMMR high-risk disease. The guideline appendix does acknowledge the varying strength of evidence across clinical scenarios, but the Viewpoint insists that the pivotal role of pelvic radiotherapy in achieving durable locoregional control, combined with the absence of robust randomized evidence demonstrating that systemic therapy alone is equivalent, means any suggestion of safe omission warrants careful scrutiny. The only randomized trial to have specifically examined omitting radiotherapy, GOG-258, predates the immunotherapy era entirely, limiting how far its findings can be carried into modern practice.

That trial, along with PORTEC-3, forms the evidentiary backbone of adjuvant decision-making, and the authors dissect both in detail. PORTEC-3 compared adjuvant chemoradiotherapy with pelvic radiotherapy alone in high-risk endometrial cancer and, in its updated 2019 analysis, demonstrated significant improvements in both failure-free survival and overall survival, each with a hazard ratio of 0.70. Crucially, the trial did not test the omission of radiotherapy: pelvic radiotherapy was present in both arms, and isolated vaginal and pelvic recurrences were exceptionally rare, at just 0.3 percent and 0.9 percent respectively, while distant metastases dominated the pattern of failure. The lesson, the authors argue, is that pelvic radiotherapy already delivers durable locoregional control, and future gains are more likely to come from better systemic therapy than from removing EBRT. PORTEC-3 also incorporated rigorous radiotherapy quality assurance and patient-reported outcome assessments, reinforcing the favorable toxicity profile of modern intensity-modulated radiotherapy (IMRT).

GOG-258 tells a different but complementary story. It compared concurrent cisplatin-based chemoradiotherapy followed by four cycles of carboplatin–paclitaxel against six cycles of carboplatin–paclitaxel alone, and found no improvement in relapse-free survival from adding radiotherapy. Yet chemoradiotherapy significantly reduced vaginal and pelvic or para-aortic nodal recurrences, while distant recurrences were more frequent—possibly influenced, the authors note, by the lower systemic treatment intensity in the combined-modality arm. These findings have led some centers to adopt sequential strategies, typically six cycles of carboplatin–paclitaxel followed by pelvic EBRT with or without vaginal brachytherapy, preserving full-dose chemotherapy while retaining the locoregional benefit. Encouraging prospective cohort and retrospective data support this approach, but it has never been prospectively compared with chemotherapy alone or with the GOG-258 regimen, and therefore cannot be considered an evidence-based standard.

Neither trial included immunotherapy, but exploratory, non-prespecified molecular subgroup analyses of both have generated important—and apparently conflicting—insights for the dMMR population. In PORTEC-3, the subgroup analysis suggested that chemotherapy added little benefit when combined with radiotherapy in dMMR tumors, whereas in GOG-258 exploratory analyses numerically favored chemotherapy over chemoradiotherapy, hinting at a limited incremental role for radiotherapy, though with wide confidence intervals. Strikingly, both trials converged on similar two-year recurrence-free survival rates of roughly 75 percent in PORTEC-3 and 73 percent in GOG-258 for stage III dMMR tumors, with no clear long-term advantage for either strategy. The authors’ verdict is that these hypothesis-generating analyses point in different directions regarding the relative contributions of chemotherapy and radiotherapy, yet converge on a single message: neither modality can be declared safely dispensable in stage III dMMR disease, and prospective molecularly stratified trials are needed.

The immunotherapy data themselves, the authors argue, do not fill this gap. The RUBY and NRG-GY018 trials enrolled patients with advanced, metastatic, or recurrent disease and high anticipated event rates—populations well suited to detecting progression-free survival benefits quickly, but very different from a purely adjuvant cohort of patients rendered disease-free by surgery. KEYNOTE-B21 did address the adjuvant setting directly, but radiotherapy was not randomized; it was delivered at investigator discretion, with approximately 73 percent of patients in the preplanned dMMR subgroup receiving adjuvant radiotherapy and about two-thirds receiving EBRT. The observed benefit of pembrolizumab, including two-year disease-free survival approaching 90 percent in the dMMR subgroup, was therefore achieved largely in the context of combined-modality treatment. The trial, the authors conclude, cannot be used either to support or to refute the independent value of radiotherapy, and certainly not to justify abolishing adjuvant chemoradiotherapy, which remains a validated standard of care.

Biology, if anything, points toward integration rather than substitution. Preclinical work summarized in the Viewpoint describes how radiotherapy may synergize with immune checkpoint inhibition by promoting the release of tumor antigens, enhancing MHC class I expression and antigen presentation, and activating innate immune pathways including the cGAS–STING/type I interferon axis, thereby priming antitumor immune responses. On the toxicity side, the authors contend that fears about pelvic radiotherapy largely stem from the era of four-field box techniques, when higher doses to bowel, bladder, and bone marrow were unavoidable. Contemporary IMRT, validated in PORTEC-3 and the RTOG 1203 trial, significantly reduces acute gastrointestinal and genitourinary toxicity, with low rates of long-term grade ≥2 toxicities and favorable patient-reported outcomes. Phase III data from KEYNOTE-A18, although generated in cervical cancer, showed improved survival when pembrolizumab was added to chemoradiotherapy without increased toxicity—and at higher radiotherapy doses than those typically used adjuvantly in endometrial disease—offering indirect reassurance about the safety of the combination.

What about simply withholding radiotherapy and reserving it for a recurrence? The authors reject this as unsupported. Data on outcomes after recurrence in molecularly defined subgroups remain limited; in a multicenter cohort by Siegenthaler and colleagues, treated largely before immunotherapy became routine, median post-recurrence survival for dMMR tumors was 43 months—meaning relapse is not uniformly lethal but remains clinically significant. Long-term PORTEC-3 results show that recurrences in dMMR tumors cluster within the first two to three years, that locoregional relapses are uncommon where upfront pelvic radiotherapy was given, and that distant metastases are the predominant pattern of failure—suggesting the critical window for locoregional intervention is the adjuvant phase itself. Recurrence also carries intrinsic costs: more intensive salvage treatment, greater cumulative toxicity, and a heavier healthcare burden.

The authors’ synthesis is measured but firm. Molecular classification has refined risk stratification, and emerging immunotherapy data in dMMR tumors are genuinely promising, but those data derive from studies in which radiotherapy was either routinely delivered or never evaluated as an independent variable. Combined chemoradiotherapy must therefore remain a foundational standard, with immunotherapy viewed as a potential addition rather than a replacement. Ongoing trials, including NRG-GY020 (NCT04214067) and the RAINBO MMRd-GREEN trial (ENGOT-en14/GREEN, NCT05255653), are expected to define the optimal integration of immunotherapy and adjuvant radiotherapy in molecularly stratified populations, ideally incorporating patterns of failure and patient-reported outcomes alongside survival. Until such evidence arrives, the authors argue, de-escalation should proceed with caution: the real challenge of the immunotherapy era is not replacing pelvic radiotherapy, but optimizing systemic disease control while preserving the durable locoregional control that modern radiotherapy already delivers.

Subject of Research: Adjuvant radiotherapy and chemo-immunotherapy in FIGO stage III mismatch repair–deficient endometrial cancer

Article Title: Adjuvant radiotherapy in FIGO stage III dMMR endometrial cancer: evidence and perspectives in the molecular era

Article References: Macchia, G., Merlotti, A., De Felice, F., Russo, D., Marchetti, C., & Lorusso, D. (2026). Adjuvant radiotherapy in FIGO stage III dMMR endometrial cancer: evidence and perspectives in the molecular era. eClinicalMedicine, 101, Article 104257. https://doi.org/10.1016/j.eclinm.2026.104257

Image Credits: AI Generated

DOI: 10.1016/j.eclinm.2026.104257

Keywords: endometrial cancer, dMMR, radiotherapy, immunotherapy, chemoradiotherapy, PORTEC-3, GOG-258, KEYNOTE-B21, pembrolizumab, ESGO-ESTRO-ESP guidelines, locoregional control, molecular classification

Endometrial cancer is among the most common malignancies of the female reproductive system, and its global incidence has climbed markedly in recent years. Roughly ninety percent of cases are caught early and respond well to surgery and chemoradiotherapy, but patients with locally advanced, recurrent, or metastatic disease often resist standard treatment and face poor outcomes. That clinical gap has pushed researchers to hunt for the molecular drivers that separate indolent tumors from aggressive ones. The new study focuses on the epitranscriptome, the layer of chemical modifications deposited onto RNA after transcription, which has emerged in the past decade as a major regulator of gene expression in health and disease.

Among these modifications, 5-methylcytosine, abbreviated m5C, is one of the most abundant marks on eukaryotic messenger RNA. Like other RNA modifications, m5C operates through a cast of enzymes and binding proteins: writer enzymes such as NSUN2 and NSUN6 install the methyl group, erasers can remove it, and reader proteins such as ALYREF recognize the mark and determine what happens to the tagged transcript. ALYREF, historically known for its role in ferrying mature mRNA out of the nucleus, binds m5C-modified sites and influences RNA stability, export, and metabolic fate. Previous work had implicated ALYREF in nasopharyngeal carcinoma, glioma, lung cancer, and bladder cancer, but its role in endometrial cancer remained uncharted.

The team began by mining several independent public datasets, including the Gene Expression Omnibus, The Cancer Genome Atlas, GTEx, and the Human Protein Atlas. Across every source, ALYREF was significantly elevated in tumor tissue compared with normal endometrium, at statistical thresholds below p = 0.001. The pattern held in paired comparisons of tumors and adjacent normal tissue from the same patients, and immunohistochemistry on clinical specimens confirmed the protein-level difference. Most strikingly, survival analysis of the TCGA endometrial carcinoma cohort showed that patients with high ALYREF expression had significantly shorter overall survival and relapse-free survival, and multivariate Cox regression established ALYREF as an independent prognostic factor after adjustment for clinicopathological variables. High ALYREF also tracked with aggressive histology, including grade 3 tumors and serous or mixed subtypes.

To test whether ALYREF actively drives the disease rather than merely marking it, the researchers manipulated its expression in endometrial cancer cell lines. Silencing ALYREF with short hairpin RNAs in HEC-1A and Ishikawa cells, which naturally express the protein at high levels, sharply reduced colony formation, cell proliferation measured by CCK-8 assays, and DNA synthesis measured by EdU incorporation. Wound healing and Transwell experiments showed impaired migration and invasion, while flow cytometry revealed G2/M cell cycle arrest and increased apoptosis. Conversely, forcing ALYREF expression in KLE cells, which normally produce little of the protein, enhanced every one of those malignant behaviors. In nude mice bearing subcutaneous xenografts, ALYREF knockdown significantly slowed tumor growth, reducing both tumor volume and final tumor weight over a 42-day observation period.

The mechanistic hunt began with an unbiased, three-pronged sequencing strategy. RNA sequencing of ALYREF-knockdown cells identified 1,890 differentially expressed genes. RNA immunoprecipitation sequencing captured 703 transcripts physically bound by ALYREF. And bisulfite sequencing tailored to detect m5C mapped 4,084 modified transcripts, revealing that the marks cluster mainly within the coding sequence of mRNAs. Intersecting all three datasets narrowed the field to 28 candidate targets, and among the ten most downregulated after ALYREF depletion, one gene stood out: XRCC6, which encodes the Ku70 subunit of the non-homologous end joining DNA repair complex. The correlation was robust at every level, from a Pearson coefficient of 0.749 between ALYREF and XRCC6 mRNAs in the TCGA cohort to a Spearman coefficient of 0.82 between the two proteins in 50 clinical tumor samples.

Rescue experiments then confirmed that XRCC6 is the functional effector of ALYREF. Restoring XRCC6 expression in ALYREF-deficient cells reversed nearly every malignant phenotype: proliferation recovered, migration and invasion returned, G2/M arrest eased, and apoptosis subsided. In xenografted mice, XRCC6 overexpression largely canceled the tumor-suppressive effect of ALYREF knockdown. The regulation itself proved to be a matter of mRNA stability rather than export. Actinomycin D chase assays showed that XRCC6 mRNA degraded much faster without ALYREF, its half-life shrinking significantly, while nuclear-cytoplasmic fractionation demonstrated that cytoplasmic levels of the transcript fell even as nuclear levels stayed constant, indicating that ALYREF protects the mRNA in the cytoplasm rather than shuttling it out of the nucleus.

The epitranscriptomic logic of the axis came into focus through experiments on the writer enzymes. When NSUN2 was silenced, XRCC6 mRNA levels dropped; knocking down NSUN6 had no effect. Crucially, in cells lacking NSUN2, additional depletion of ALYREF produced no further reduction in XRCC6, showing that the methyl mark is a prerequisite for ALYREF’s action. Bisulfite sequencing and integrative genomics viewer analysis revealed distinct m5C peaks on the XRCC6 transcript that overlapped precisely with ALYREF binding regions. Reporter assays drove the point home: mutating the methylated sites abolished ALYREF’s suppressive effect on luciferase activity driven by the XRCC6 sequence. Mutating either of two adjacent m5C sites in the coding region partially weakened ALYREF binding and mRNA stability, but mutating both together caused a synergistic collapse, suggesting the two sites operate cooperatively as a local recognition module, a model the authors note will require structural biology to fully confirm.

Downstream, the chain terminates at Wnt/β-catenin signaling, a pathway central to development and frequently hijacked in cancer. ALYREF knockdown drained β-catenin from the nucleus of HEC-1A cells and reduced levels of the Wnt target c-Myc, while XRCC6 overexpression restored both. Notably, co-immunoprecipitation found no direct physical interaction between XRCC6 and β-catenin, implying that XRCC6, a multifunctional nuclear protein, promotes β-catenin transcriptional output indirectly, perhaps by shaping nuclear co-activator complexes or chromatin accessibility. TOP/FOP Flash reporter assays confirmed that XRCC6 boosts β-catenin/TCF-dependent transcription, and canonical Wnt target genes such as AXIN2 and CCND1 fell when ALYREF was silenced. The decisive experiment used XAV-939, a pharmacological Wnt inhibitor: the drug largely blocked the proliferative rescue that XRCC6 overexpression conferred on ALYREF-deficient cells, proving the oncogenic phenotype depends on intact Wnt signaling.

The authors are candid about the study’s limits. Clinical protein validation relied on a single-center retrospective cohort of modest size, the cell line models do not capture the full genomic heterogeneity of TCGA molecular subtypes such as POLE-ultramutated or mismatch-repair-deficient tumors, and the work examined cell-autonomous regulation without probing interactions with cancer-associated fibroblasts or immune cells. Even so, the findings delineate a complete oncogenic axis, ALYREF to m5C to XRCC6 to Wnt/β-catenin, and broaden a growing picture in which ALYREF’s downstream targets differ sharply from one cancer type to another. Because XRCC6 plays dual roles in DNA damage repair and Wnt signaling, patients whose tumors show high ALYREF/XRCC6 expression might ultimately benefit from therapies aimed at either pathway, an idea that now rests on a solid mechanistic foundation and awaits prospective, multicenter testing.

Subject of Research: The role of the m5C reader protein ALYREF in promoting endometrial cancer progression through XRCC6-mediated Wnt/β-catenin signaling

Article Title: m5C Reader ALYREF Promotes the Progression of Endometrial Cancer by Activating the XRCC6‐Mediated Wnt/β‐catenin Signaling Pathway

Article References: Hao, L., Zhang, J., Qian, Q., Jiang, M., Liu, Y., Geng, Y., Cui, N., Guo, Q., & Guo, J. (2026). m 5 C Reader ALYREF Promotes the Progression of Endometrial Cancer by Activating the XRCC6‐Mediated Wnt/β‐catenin Signaling Pathway. Advanced Science, Article e77548. https://doi.org/10.1002/advs.77548

Image Credits: AI Generated

DOI: 10.1002/advs.77548

Keywords: endometrial cancer, ALYREF, m5C, epitranscriptomics, XRCC6, Wnt/β-catenin signaling, NSUN2, RNA modification, mRNA stability, Ku70, prognostic biomarker, Advanced Science

Endometrial cancer is the most common gynecologic malignancy in developed countries, and its incidence is rising, driven in part by obesity and changing reproductive patterns. For younger patients who hope to preserve their fertility, the standard alternative to hysterectomy is progestin therapy, typically high-dose medroxyprogesterone acetate, which can induce tumor regression and allow pregnancy. The catch is resistance: a substantial fraction of tumors either fail to respond from the outset or relapse after an initial remission, forcing patients toward definitive surgery. Clinicians have long sought molecular clues that predict who will respond and interventions that convert non-responders into responders. The Shinshu team, led by Natsuki Uchiyama and corresponding author Ryoichi Asaka, approached both questions through the lens of tumor metabolism.

ME1 occupies a strategically important position in cellular biochemistry. The enzyme decarboxylates malate to pyruvate while reducing NADP+ to NADPH, a molecule that functions as the cell’s principal reducing currency. NADPH feeds fatty acid and cholesterol synthesis and, critically, powers antioxidant systems such as glutathione reductase that neutralize reactive oxygen species, the chemically aggressive byproducts of aerobic metabolism. Cancer cells, which run biosynthetic pathways at full throttle while enduring metabolic stress, often become dependent on NADPH-generating enzymes. That dependence creates a therapeutic window: inhibit the enzyme, and the tumor cell is caught between a shortage of building blocks and an inability to defuse its own oxidative waste. Until this study, however, ME1’s role in endometrial carcinoma was essentially unmapped.

To chart that map, the researchers performed immunohistochemistry on surgical specimens from 172 patients with endometrioid endometrial carcinoma, alongside six samples of normal endometrium. The staining revealed a clear pattern: ME1 protein was significantly more abundant in tumor tissue than in healthy endometrium. When the team stratified patients by expression intensity, using an H-score threshold of 75.66, they found that tumors with high ME1 were independently associated with shorter progression-free survival, with a hazard ratio of 1.89 and a 95 percent confidence interval of 1.07 to 3.34, reaching statistical significance at P equals 0.028. Because the analysis controlled for other clinical variables, the result suggests ME1 is not merely a passenger marker of aggressive disease but a feature that tracks with, and may contribute to, clinical behavior.

The next step was mechanistic. Working with endometrial cancer cell lines in vitro, the researchers suppressed ME1 two ways: genetically, using small interfering RNA to degrade the enzyme’s messenger RNA, and pharmacologically, using a small-molecule inhibitor. Both approaches curtailed proliferation across every cell line tested, confirming that these cells rely on ME1 for growth. But the most consequential findings emerged in Ishikawa cells, a line that expresses the progesterone receptor, the molecular gatekeeper through which medroxyprogesterone acetate exerts its antiproliferative effects. When ME1 was inhibited in these cells, reactive oxygen species accumulated, and, unexpectedly, the progesterone receptor itself was upregulated. The tumor was, in effect, being re-sensitized to the drug by two complementary routes: oxidative stress pushed it toward the brink, while increased receptor expression gave the progestin more targets to engage.

To quantify how well the two agents worked together, the team applied the Bliss independence model, a standard framework for drug synergy in which a score above zero indicates that the combination outperforms what the individual drugs would achieve additively. The maximum delta-Bliss score reached 0.51, a value indicating strong synergy between ME1 inhibition and medroxyprogesterone acetate. In practical terms, the combination suppressed cell proliferation far more effectively than either treatment alone, and the effect was most pronounced in the progesterone receptor-positive setting where the progestin has a pathway to act. This dual mechanism, ROS accumulation paired with receptor upregulation, offers a coherent explanation for a phenomenon that has puzzled clinicians: why some progesterone receptor-low tumors resist progestin therapy despite otherwise treatable disease.

Cell culture, however, is a simplified world, so the investigators moved to a xenograft model, transplanting endometrial cancer cells into mice and treating the animals with the ME1 inhibitor, medroxyprogesterone acetate, or both. The combination suppressed tumor growth more effectively than either single agent, and, importantly, the treated animals showed no apparent toxicity. That safety signal matters because progestin therapy is chosen precisely to spare young patients the reproductive and surgical consequences of hysterectomy; an add-on drug that imposed heavy side effects would undermine the strategy’s purpose. The in vivo result, while preliminary, suggests that metabolic sensitization could be layered onto existing hormonal regimens without unacceptable cost to the patient.

The study’s implications extend in two directions. As a prognostic tool, ME1 immunohistochemistry could eventually help clinicians stratify patients at diagnosis, identifying those with high-expression tumors who might need closer monitoring or earlier escalation rather than extended courses of progestin that are destined to fail. As a therapeutic target, ME1 inhibition offers a rational combination partner for progestin therapy, potentially converting resistant tumors into responsive ones. The concept fits within a broader movement in oncology that treats metabolic enzymes, once considered housekeeping proteins, as actionable dependencies, a strategy that has already yielded drugs against enzymes in nucleotide synthesis and one-carbon metabolism. ME1’s role in supplying NADPH makes it part of the same family of vulnerabilities.

Caution is warranted before clinical translation. The pharmacological inhibitor used in the study is an experimental tool, not an approved drug, and the xenograft model, though informative, cannot fully reproduce the hormonal and immune environment of the human endometrium. The patient cohort was retrospective, and the survival association, while statistically significant, will need validation in independent and prospective cohorts. Dosing, scheduling, and patient selection for any future combination trial remain open questions, as does the question of whether ME1 inhibition would benefit tumors with low progesterone receptor expression, where the progestin sensitization mechanism may not apply. The authors received no external funding for the work and declare no conflicts of interest, and the study was approved by the ethics committee of Shinshu University School of Medicine.

Even with those caveats, the research delivers a satisfying arc from bench to bedside logic: an enzyme is overexpressed in tumors, its abundance predicts worse outcomes, its suppression stresses cancer cells and raises the very receptor that hormonal therapy depends on, and the combination outperforms either approach alone in living animals. For the growing population of young women facing endometrial cancer who want to preserve their fertility, the prospect of a metabolic drug that makes progestin therapy work more reliably is more than an incremental finding. It reframes treatment resistance not as an immutable property of the tumor but as a metabolic state that can be chemically reversed. Larger trials will decide whether ME1 inhibitors can fulfill that promise, but the Shinshu study has supplied the biological rationale, the prognostic evidence, and the preclinical proof of concept in a single, coherent package.

Subject of Research: Malic enzyme 1 as a prognostic marker and therapeutic target for enhancing progestin sensitivity in endometrioid endometrial carcinoma

Article Title: Malic enzyme 1 is a prognostic factor and a therapeutic target to enhance progestin sensitivity in endometrial cancer

Article References: Uchiyama, N., Asaka, R., Fujioka, M., Kamijo, K., Yokokawa, Y., Shinagawa, M., Nakajima, M., Takeuchi, H., Ando, H., & Miyamoto, T. (2026). Malic enzyme 1 is a prognostic factor and a therapeutic target to enhance progestin sensitivity in endometrial cancer. Journal of Cancer Research and Clinical Oncology. https://doi.org/10.1007/s00432-026-06633-3

Image Credits: AI Generated

DOI: 10.1007/s00432-026-06633-3

Keywords: endometrial cancer, malic enzyme 1, ME1, progestin therapy, medroxyprogesterone acetate, progesterone receptor, reactive oxygen species, NADPH, fertility-sparing therapy, tumor metabolism, drug synergy, prognostic marker

Incretins occupy a central position in the entero-insular axis, the signalling network by which the gut primes the pancreas to release insulin after a meal in a glucose-dependent manner. GLP-1, a 30-amino-acid polypeptide secreted by L cells of the terminal ileum and colon, binds a G protein-coupled receptor distributed across pancreatic islets, adipose tissue, the cardiovascular system, the central nervous system and, crucially, the reproductive organs. Its classical action involves activation of the cAMP/PKA cascade in pancreatic beta cells, enhancing insulin gene transcription and glucose-dependent insulin secretion. The hormone also regulates voltage-dependent calcium channels to promote calcium influx, suppresses glucagon release from alpha cells, and engages the PI3K pathway to sharpen peripheral insulin sensitivity.

The molecular picture has grown considerably richer in recent years. Researchers identified the adipokine zinc-alpha2-glycoprotein as a possible mediator of the metabolic benefits of GLP-1 receptor agonists, with twelve weeks of liraglutide treatment significantly elevating circulating ZAG levels in patients with type 2 diabetes. Other teams have explored ways to boost the body’s own GLP-1 output: the dietary compound imperatorin and glycyrrhizic acid, a principal component of licorice, both activate the TGR5 receptor to enhance GLP-1 secretion in experimental models. Even receptor architecture is proving malleable—bioluminescence resonance energy transfer studies revealed that the GLP-1 receptor can form heterodimers with the secretin receptor in islet cells, altering calcium signalling and inducing cross-desensitisation between the two receptors.

GIP, the second major incretin, is a 42-amino-acid peptide produced by K cells in the duodenum and jejunum. Though less intensively studied than GLP-1, it promotes insulin biosynthesis, supports beta-cell differentiation and survival, and enhances fat storage and bone formation. Work by Samms and colleagues showed that GIP enhances lipoprotein lipase activity in adipocytes through a PI3K/PKB-LKB1/AMPK-TORC2 signalling axis, promoting lipid uptake and storage while increasing insulin sensitivity. Intriguingly, GIP and GLP-1 signalling appear intertwined: N-glycosylation-deficient GIP receptors can be functionally rescued by co-expression with wild-type GLP-1 receptors, hinting at functional heterodimerisation between the two receptor classes.

The most clinically mature application in gynaecology is polycystic ovary syndrome, a condition characterised by hyperandrogenemia and insulin resistance that affects a growing number of women worldwide. Studies have confirmed abnormal secretion of both GIP and GLP-1 in patients with PCOS, and clinical research has shown that GLP-1 receptor agonists such as liraglutide and semaglutide can improve menstrual regularity, raise ovulation rates and reduce body fat. Mechanistically, the agonist exenatide was found to improve insulin resistance in PCOS rats by activating the AMPKalpha-SIRT1 pathway, while GLP-1 receptor agonists more broadly bolster antioxidant defences via the Nrf2/ARE pathway and reduce endoplasmic reticulum stress through modulation of the PERK pathway.

Genetic evidence adds weight to the GIP connection. A two-sample Mendelian randomisation analysis found that genetic activation of the GIP receptor is associated with a reduced risk of PCOS, and animal work shows that GIP signalling regulates the oestrous cycle and female fertility through the pituitary-gonadal axis. The gut microbiome may also be a critical link: dysbiosis in PCOS elevates the microbial metabolite agmatine, which activates the farnesoid X receptor and suppresses GLP-1 secretion from intestinal L cells, contributing to insulin resistance and ovarian dysfunction. This agmatine-FXR-GLP-1 axis offers a compelling explanation for how gut health, metabolism and reproduction converge in the syndrome.

Beyond the ovary, incretins display striking anti-inflammatory and anti-fibrotic properties with direct relevance to uterine disease. GLP-1 suppresses macrophage inflammatory factors including IL-1beta, IL-6 and TNF-alpha, and gene therapy studies in obese diabetic mice showed reduced macrophage infiltration of adipose tissue and inhibition of NF-kappaB and JNK signalling. In models of intrauterine adhesion, semaglutide alleviated fibrosis and inflammation by modulating NF-kappaB and reducing fibrotic markers such as ACTA2, COL1A1 and FN, while dulaglutide improved endometrial thickness and reduced collagen deposition by suppressing M1 macrophage polarisation and the TGF-beta/Smad2 pathway. Preclinical studies likewise suggest GLP-1 receptor agonists can inhibit the proliferation of ectopic endometrial cells in endometriosis through PI3K/Akt and NF-kappaB pathways.

The anti-tumour signals are tantalising but preliminary. In endometrial cancer cell lines, liraglutide inhibited proliferation in a time- and concentration-dependent manner, activating AMPK, upregulating progesterone receptors and synergising with medroxyprogesterone acetate. Autophagy appears central: liraglutide induced autophagic cell death by increasing LC3 expression and p-AMPKalpha while decreasing SQSTM1. For ovarian cancer, GLP-1 receptor expression has been documented in some tumour tissues, and agonists can curb proliferation and invasion via AMPK in vitro—but the authors are careful to stress that these anti-tumour effects may be partly secondary to weight loss and improved metabolic status, and direct effects require clinical validation.

Perhaps the most conceptually ambitious frontier is the brain-gut axis. Incretins directly modulate the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes, and electrophysiological recordings show GLP-1 acting on GnRH neurons to increase firing rates and GABAergic synaptic input. GLP-1 receptor agonists may increase pulsatile GnRH release via the hypothalamic kisspeptin system, influencing luteinising hormone secretion, while peripherally promoting follicular development and oocyte maturation through effects on theca cells. GIP receptor knockout mice exhibit disrupted oestrous cycles and reduced fertility, underscoring GIP’s non-redundant role. Notably, a dual GLP-1/oestrogen agonist improved ovarian cyclicity and insulin sensitivity in PCOS mouse models without direct estrogenic proliferative effects on the uterus.

Clinical translation, however, demands caution. Combination therapy with metformin outperforms metformin alone for weight, BMI and insulin sensitivity, and semaglutide reduced lingual fat in women with PCOS in a randomised trial—yet adverse events are more frequent with combination regimens, and real-world data show 17.8% of patients are non-responders to semaglutide or liraglutide for obesity. Gastrointestinal symptoms remain the most common side effects, and safety concerns persist regarding gallbladder disorders, pancreatitis and rodent C-cell findings. Use in pregnancy and lactation is not recommended, with regulators advising contraception and a two-month washout before conception. For endometriosis, intrauterine adhesions and gynaecological cancers, the evidence remains almost entirely preclinical. The authors call for large, multicentre randomised trials with reproductive outcomes as primary endpoints, dedicated exploration of dual GIP/GLP-1 agonists such as tirzepatide, and tissue-specific studies to disentangle direct hormonal actions from the indirect fruits of metabolic improvement. Incretin-based therapy, they conclude, represents a promising interdisciplinary bridge between endocrinology and gynaecology—one whose full span has yet to be built.

Subject of Research: The role and mechanisms of the incretin hormones GLP-1 and GIP in gynaecological diseases

Article Title: The Role and Mechanism of Incretins in Gynaecologic Diseases

Article References: Yan, J., Cao, M., Ding, Y., Zhang, Y., Sun, Y., Jiang, G., Zhang, Y., Kang, L., Zhou, X., Luo, J., & Li, B. (2026). The Role and Mechanism of Incretins in Gynaecologic Diseases. Endocrinology, Diabetes & Metabolism, 9(5), Article e70340. https://doi.org/10.1002/edm2.70340

Image Credits: AI Generated

DOI: 10.1002/edm2.70340

Keywords: incretins, GLP-1, GIP, polycystic ovary syndrome, endometrial cancer, endometriosis, intrauterine adhesions, insulin resistance, brain-gut axis, GLP-1 receptor agonists, semaglutide, women's health

The experimental agent, known as E7386, belongs to a relatively new class of medicines called protein–protein interaction inhibitors. Rather than blocking an enzyme’s active site, it physically prevents the CREB-binding protein (CBP) from docking with β-catenin, a transcriptional co-activator that sits at the heart of the Wnt signalling pathway. When the CBP–β-catenin interaction proceeds unchecked, tumour cells receive a continuous stream of pro-growth and pro-survival instructions. Preclinical work had shown that E7386 suppressed intestinal polyp formation in genetically predisposed mice and shrank tumours in models where the Wnt pathway was overactive, and that combining the drug with lenvatinib — a multi-kinase inhibitor that starves tumours of their blood supply — produced greater antitumour activity than either drug alone in endometrial cancer models, regardless of whether tumours carried mutations in the CTNNB1 gene that encodes β-catenin.

The clinical context is stark. Endometrial cancer incidence is rising worldwide, and while the addition of immunotherapy to first-line chemotherapy has transformed outcomes for many patients, roughly 15 percent of women are diagnosed with advanced-stage disease, for whom five-year survival hovers around 15 to 17 percent. Once a patient’s tumour progresses after platinum-based chemotherapy and an anti-PD-(L)1 immune checkpoint inhibitor, second-line chemotherapy regimens deliver response rates of only about 15 percent. Antibody–drug conjugates have shown encouraging activity in this setting, but they require intravenous infusion and raise concerns about cross-resistance between agents sharing similar payloads, creating a genuine need for orally administered alternatives.

Study 102 enrolled 30 women between January 2023 and May 2024 across 12 sites in Japan, the Republic of Korea, and the United States. All had advanced, unresectable, or recurrent endometrial cancer that had progressed on or after platinum chemotherapy and an anti-PD-(L)1 agent such as pembrolizumab, durvalumab, or dostarlimab. Sixteen of the 30 had already been treated with lenvatinib itself. Participants received E7386 at 120 milligrams twice daily, with the lenvatinib starting dose later reduced from 20 to 14 milligrams once daily after non-clinical data suggested the combination retained its potency even at the lower dose — a change that also widened access for patients previously exposed to the drug.

The efficacy results exceeded what the heavily pretreated population would normally be expected to achieve. Eleven patients had confirmed responses — one complete and ten partial — for an objective response rate of 36.7 percent, roughly double the activity of conventional second-line chemotherapy. Responses proved durable, with a median duration of 9.1 months, and the disease control rate, which counts stable disease as well as shrinkage, reached 70 percent. Median progression-free survival was 5.5 months overall, and median overall survival had not been reached at the data cut-off, with 70 percent of patients alive at both six and twelve months.

The subgroup breakdown was particularly striking. Among the 14 women who had never received lenvatinib, the objective response rate climbed to 57.1 percent, with a median progression-free survival of 10.8 months — figures that compare favourably even with recent antibody–drug conjugate trials in the post-immunotherapy setting. Perhaps more surprising, three of the 16 patients who had already been treated with lenvatinib also responded, including two whose most recent prior therapy had been lenvatinib combined with pembrolizumab. This suggests that E7386 may re-sensitise tumours to lenvatinib’s mechanism, potentiating its antitumour activity rather than simply adding an independent effect.

Safety data supported the combination’s feasibility. Every patient experienced some treatment-emergent adverse event, but the most common — vomiting in 73.3 percent and nausea in 66.7 percent — were predominantly grade 1 or 2 and were largely controlled with standard anti-nausea medications such as 5-HT3 receptor antagonists. No grade 4 or 5 events occurred, and only two patients discontinued treatment because of toxicity. Dose interruptions and reductions were common, particularly for lenvatinib, reflecting the familiar fingerprint of that drug: proteinuria, diarrhoea, and hand–foot skin reactions appeared at rates consistent with its established profile. Because agents targeting the Wnt pathway have previously been linked to bone fragility, the investigators monitored bone density and bone turnover markers throughout; bone events occurred in just three patients, all manageable with supplements or antiresorptive therapy.

Biomarker analyses added a layer of molecular context. Circulating tumour DNA sequencing at baseline identified TP53 mutations as the most frequent alteration, present in 46.7 percent of patients, followed by mutations in KRAS, PIK3CA, PPP2R1A, PTEN, and FBXW7. Notably, a multivariate analysis adjusting for age, mismatch repair status, and prior lenvatinib exposure found no association between TP53 mutation status and any clinical outcome, and responses were seen across mismatch repair proficient and deficient tumours alike. With only 30 participants, however, the study was not powered to detect subtle predictive signatures, and the authors caution that the molecular findings are exploratory.

The trial’s limitations are real but typical of early-phase oncology research: a single-arm design without a control group, a small sample concentrated at Asian sites, and a population skewed toward patients with good performance status. Even so, the enrolled cohort closely mirrors the real-world post-immunotherapy population, with more than 80 percent having received at least two prior lines of systemic therapy. Against benchmarks such as the roughly 15 percent response rate of second-line chemotherapy, the 21 percent of lenvatinib monotherapy, and the 22 percent of sacituzumab govitecan in a mixed immunotherapy-exposed population, the 36.7 percent response rate — and 57.1 percent in lenvatinib-naïve patients — stands out.

The programme is already moving forward. A randomised dose-optimisation phase is now enrolling a more geographically balanced population of lenvatinib-naïve patients with advanced endometrial carcinoma, comparing two doses of E7386 plus lenvatinib against lenvatinib monotherapy or physician’s choice chemotherapy with doxorubicin or paclitaxel. If those results confirm the signals seen here, an all-oral regimen targeting the Wnt pathway and tumour vasculature could become a genuinely new option for women who currently have none — and a demonstration that drugging protein–protein interactions, long considered near-impossible, is becoming practical medicine.

Subject of Research: E7386 plus lenvatinib for advanced endometrial cancer after platinum chemotherapy and anti-PD-(L)1 immunotherapy

Article Title: E7386 plus lenvatinib in patients with advanced endometrial cancer that progressed on platinum-based chemotherapy and an anti-PD-(L)1 immunotherapy: a single-arm, open-label, global phase 1b/2 dose-expansion cohort

Article References: Lee, J.-Y., Hasegawa, K., Kim, B.-G., Berman, B., Suzuki, S., Corr, B., Yunokawa, M., Orr, D., Yamamoto, N., Soliman, P. T., Miller, D. S., Potdar, A. A., Sahara, T., Kimura, T., Dutta, L., Wu, J., McKenzie, J., & Kyi, C. (2026). E7386 plus lenvatinib in patients with advanced endometrial cancer that progressed on platinum-based chemotherapy and an anti-PD-(L)1 immunotherapy: a single-arm, open-label, global phase 1b/2 dose-expansion cohort. eClinicalMedicine, 100, Article 104206. https://doi.org/10.1016/j.eclinm.2026.104206

Image Credits: AI Generated

DOI: 10.1016/j.eclinm.2026.104206

Keywords: endometrial cancer, E7386, lenvatinib, CBP–β-catenin inhibitor, Wnt signalling, immunotherapy resistance, phase 1b/2 trial, anti-PD-(L)1, targeted therapy, protein–protein interaction inhibitor, progression-free survival, gynecologic oncology

Fgl-1 has attracted growing attention in cancer biology in recent years, largely because of its dual identity. Originally characterized as a hepatokine, a secreted protein produced mainly by the liver with roles in metabolism and inflammation, it was later recognized as an emerging immune checkpoint ligand. When expressed on the surface of tumor cells, Fgl-1 can bind to lymphocyte activation gene 3, known as LAG-3, on T cells, thereby suppressing the immune response against the tumor. In hepatocellular carcinoma, Fgl-1 has been shown to promote the exhaustion of liver-resident memory T cells, helping the tumor evade immune surveillance. But the protein appears to be more than a decoy for immune cells. Prior work in gastric cancer linked Fgl-1 overexpression to invasion, metastasis and poor prognosis, while studies in metabolic disease connected circulating levels of the protein to insulin resistance and obesity. What remained unclear until now was its clinicopathological significance and oncogenic role in endometrial adenocarcinoma specifically.

To address this gap, the Shandong team first examined Fgl-1 expression in human tissue samples using immunohistochemistry, a staining technique that reveals where and how strongly a protein is produced in tissue sections. The results were unambiguous. Fgl-1 was significantly overexpressed in endometrial adenocarcinoma tissues relative to normal endometrial tissue, a difference that reached high statistical significance, and the level of expression correlated positively with tumor grade, meaning that more aggressive, less differentiated tumors tended to produce more of the protein. This grade association hints that Fgl-1 is not merely a passenger marker of malignant transformation but may actively participate in the biological escalation of the disease.

The investigators then turned to cell lines to probe function. Western blotting, which detects specific proteins in cell lysates, confirmed that Fgl-1 was abundantly produced in endometrial adenocarcinoma cell lines, with particularly high levels in two lines, HEC1B and KLE. These became the workhorses of the study. Using lentiviral vectors, short fragments of genetic material delivered by engineered viruses that silence a target gene, the researchers knocked down Fgl-1 expression by roughly 60 percent. The consequences were dramatic. With Fgl-1 suppressed, the cancer cells lost much of their malignancy in vitro: they became less viable, proliferated more slowly, formed fewer cell clones in colony-formation assays, migrated less effectively across scratched wound-healing cultures, and invaded less aggressively through extracellular-matrix-coated membranes.

To understand how a single secreted protein could exert such broad control over cancer cell behavior, the team examined the molecular circuits downstream of Fgl-1, focusing on two well-known hallmarks of malignant progression: the PI3K/AKT pathway and epithelial-mesenchymal transition. The PI3K/AKT cascade is one of the most frequently dysregulated signaling networks in human cancer, functioning as a central conduit for growth factor signals that promote cell survival, growth, metabolism and motility. When phosphoinositide 3-kinase is activated at the cell membrane, it recruits and activates AKT, a kinase that phosphorylates dozens of downstream targets, tipping the balance toward survival and proliferation while blocking programmed cell death. Western blot analysis in the study showed that silencing Fgl-1 inhibited PI3K/AKT signaling in KLE cells, providing direct evidence that Fgl-1 acts upstream of this pathway in endometrial cancer cells.

The second circuit, epithelial-mesenchymal transition, or EMT, is the process by which epithelial cancer cells shed their adhesive, stationary identity and acquire the motile, invasive characteristics of mesenchymal cells. EMT is orchestrated by transcription factors that repress epithelial markers such as E-cadherin and induce mesenchymal markers such as N-cadherin and vimentin, and it is a critical step in a tumor’s ability to invade surrounding tissue and seed metastases. By assessing EMT-associated proteins with Western blotting, the researchers found that suppressing Fgl-1 dampened EMT, explaining, at least in part, the reduced migration and invasion observed in the functional assays. Together, the data sketch a coherent mechanism: Fgl-1 overexpression activates PI3K/AKT signaling, which in turn drives EMT and the aggressive behaviors that accompany it.

The therapeutic implications are considerable, and they cut across two of the most active frontiers in oncology. First, because Fgl-1 functions as an immune checkpoint ligand through its interaction with LAG-3, it sits at the center of a rapidly expanding drug development effort. LAG-3 has emerged as a promising inhibitory immune checkpoint, and clinical trials of LAG-3 inhibitors, including studies combining agents such as ieramilimab with anti-PD-1 antibodies, are already underway in advanced malignancies. Immunotherapy approaches targeting PD-1 and PD-L1 have shown activity in endometrial cancer, and the field is actively searching for additional checkpoint axes that could extend these benefits to more patients. If Fgl-1 is both an immunosuppressive ligand and an intrinsically oncogenic driver in endometrial adenocarcinoma, blocking it could deliver a double blow: releasing the brakes on antitumor immunity while simultaneously strangling the PI3K/AKT-driven growth program inside the tumor cells themselves.

Second, the findings place Fgl-1 within a growing family of proteins that bridge inflammation, metabolism and cancer. Fibrinogen-like protein 1 has been implicated as a biomarker of disease activity in rheumatoid arthritis, as a contributor to T-cell exhaustion in liver cancer, and as a circulating hepatokine altered after bariatric surgery. This pleiotropy raises both opportunities and cautions. A protein that operates across so many physiological contexts may be a valuable drug target precisely because it sits at a hub of disease-relevant signaling, but systemic interference could carry metabolic or inflammatory consequences that will need careful evaluation. The new study does not address those questions directly, and its conclusions rest on correlation in tissue samples and experiments in cell culture rather than animal models or clinical intervention, so translating Fgl-1 blockade into a safe therapy remains a distant goal. Nonetheless, the demonstration that Fgl-1 suppression is sufficient to cripple key malignant behaviors in endometrial cancer cells provides a strong mechanistic rationale for pursuing such strategies.

For patients with endometrial adenocarcinoma, the study’s most immediate significance may lie in biomarker development. Because Fgl-1 expression correlates with tumor grade, it could potentially serve as a pathology-based indicator of aggressiveness, helping clinicians stratify risk and tailor surveillance intensity. The authors suggest that targeting the Fgl-1 pathway represents a promising therapeutic strategy for endometrial adenocarcinoma immunotherapy, and the convergence of their functional data with the broader clinical momentum behind LAG-3 blockade makes that suggestion more than wishful thinking. The research was supported by grants from the Science and Technology Development Program of Jinan, the Shandong Provincial Key Research and Development Program, and the Natural Science Foundation of Shandong Province, and it was conducted with ethics approval and informed consent from all tissue donors. As endometrial cancer incidence continues to rise in many parts of the world, driven in part by rising obesity rates, the discovery that a metabolic, immune-modulating, pro-oncogenic protein sits at the heart of the disease’s progression offers a timely and compelling new target for the next generation of treatments.

Subject of Research: The oncogenic role of fibrinogen-like protein 1 in endometrial adenocarcinoma progression via PI3K/AKT signaling

Article Title: Fgl-1 promotes the progression of endometrial adenocarcinoma through PI3K/AKT signal pathway

Article References: Fgl-1 promotes the progression of endometrial adenocarcinoma through PI3K/AKT signal pathway. (n.d.). https://doi.org/10.1007/s12032-026-03375-7

Image Credits: AI Generated

DOI: 10.1007/s12032-026-03375-7

Keywords: endometrial adenocarcinoma, Fgl-1, fibrinogen-like protein 1, PI3K/AKT signaling, epithelial-mesenchymal transition, immune checkpoint, LAG-3, cancer immunotherapy, tumor progression, oncogenic driver, cell invasion, biomarker

The editorial’s central claim is provocative in its simplicity: for women’s cancers, the most powerful tool available to medicine may not be a new drug, a novel biomarker, or a next-generation sequencing platform, but the knowledge that already exists and has not been fully acted upon. Oncology, De Vivo observes, is drawn toward what is mysterious or technologically complex. Yet the four major women’s cancers repeatedly demonstrate that the limiting factor is rarely the science itself. More often, it is political will, health infrastructure, and the distribution of attention and resources that determine whether established interventions actually reach the women who need them.

Cervical cancer is presented as the clearest and most consequential example. Human papillomavirus vaccination combined with modern screening can render this cancer almost entirely preventable. Where these tools are implemented equitably, incidence and mortality plummet; where they are not, women—especially those who are poor, rural, or otherwise marginalized—continue to die of a disease for which effective prevention has existed for years. The editorial is blunt about what this means: the science is not the bottleneck. The failure is one of delivery, and it is measured in lives that could have been saved with vaccines and screening programs that already work.

Breast cancer tells a more complicated story, one of genuine progress shadowed by persistent gaps. Survival has improved substantially, and the understanding of tumor biology has become more nuanced, enabling increasingly targeted therapies. But the editorial highlights a set of unresolved problems that precision medicine has not solved: public confusion about screening remains widespread, investment in primary prevention is limited, and racial and socioeconomic disparities in stage at diagnosis and outcomes persist. De Vivo draws a pointed contrast—clinicians and researchers speak about precision treatment with ease, yet remain far less precise about prevention and about who actually has access to the best care. The implication is that the same rigor applied to molecular subtyping needs to be applied to the social and structural determinants that shape who is diagnosed late and who dies early.

Ovarian cancer represents a different kind of missed opportunity, one that occurs earlier in the disease pathway. Unlike cervical cancer, it lacks an effective population-level strategy for early detection, and primary prevention options beyond women with known high-risk mutations or surgical indications remain elusive. Symptoms are typically vague and easily dismissed, care is frequently delayed, and the epidemiological lens on modifiable risk factors is comparatively underused. The editorial suggests that this underuse is itself a choice—one that reflects where research funding and clinical attention have historically flowed rather than any inherent limit on what epidemiology can contribute. For a cancer so often detected at advanced stages, the potential value of better understanding modifiable risk is difficult to overstate.

Endometrial cancer, the most common gynecologic malignancy in many high-income countries, is the fourth pillar of the argument—and perhaps the most alarming. Its incidence is rising, particularly among younger and minoritized women, and the drivers are well characterized: obesity, metabolic health, hormonal exposures, and body weight across the life course all play central roles. In principle, this should make endometrial cancer a model disease for prevention, a cancer whose trajectory could be bent downward through interventions on known risk factors. Instead, the editorial notes, it remains under-recognized, and stark racial inequities in mortality reveal that access to care, clinician bias, and delayed diagnosis are literally life-and-death issues. A preventable cancer is becoming more common, and the burden is falling disproportionately on the women least equipped to bear it.

Across all four cancers, the editorial identifies a consistent set of themes. Risk factors are, to a meaningful degree, modifiable. Tools that demonstrably work are not equitably delivered. And women’s voices remain underrepresented when research priorities are set and health policy decisions are made. These are not independent problems; they reinforce one another. When the populations most affected by a disease have the least influence over how resources are allocated, the interventions that exist tend to be deployed where they are easiest to deliver rather than where they are most needed. The result is a persistent gap between what medicine knows and what patients experience.

The editorial also serves as a progress report on a concrete effort to change that dynamic. In 2025, Cancer Causes & Control launched a dedicated collection on women’s cancers, aiming to bring these issues into sharper focus. Now in its second year, the collection has drawn strong engagement from researchers, clinicians, and advocates—evidence, De Vivo writes, that there is both energy and appetite for this work. But she is careful to distinguish engagement from impact. The challenge ahead, as she frames it, is to convert that energy into action: to move from describing disparities to dismantling them, and from documenting risk factors to actually preventing disease. Description, in other words, is a necessary but insufficient stage; the standard the journal must now hold itself to is measurable change.

That framing carries implications well beyond a single journal or collection. For researchers, it suggests that studies quantifying yet another disparity or confirming yet another risk association should be designed with an explicit pathway toward intervention. For clinicians, it underscores that prevention counseling, equitable screening outreach, and attention to the social circumstances of patients are not peripheral to oncology but central to it. For policymakers, the message is starker still: the tools to prevent cervical cancer outright, to reduce breast cancer disparities, and to slow the rise of endometrial cancer already exist, and the cost of inaction is counted in preventable deaths. What remains is the harder work of building the infrastructure, funding the programs, and sustaining the political commitment to deliver them.

De Vivo closes with a standard that is both an aspiration and an accountability measure: women deserve nothing less than the full application of what is already known. The editorial does not call for a scientific breakthrough. It calls for something arguably more difficult—the alignment of existing knowledge, existing tools, and existing evidence with the populations that need them most. In an era when cancer research is often celebrated for its technological sophistication, the argument lands with unusual force. The power to prevent many women’s cancers is not waiting to be discovered. It is waiting to be used.

Subject of Research: Prevention and health equity in women's cancers, including cervical, breast, ovarian, and endometrial cancer

Article Title: Letter from the Editor-in-Chief: Women’s cancers and the power we are not yet using

Article References: De Vivo, I. (2026). Letter from the Editor-in-Chief: Women’s cancers and the power we are not yet using. Cancer Causes & Control, 37(9), Article 154. https://doi.org/10.1007/s10552-026-02233-1

Image Credits: AI Generated

DOI: 10.1007/s10552-026-02233-1

Keywords: women's cancers, cervical cancer, breast cancer, ovarian cancer, endometrial cancer, HPV vaccination, cancer prevention, health disparities, cancer screening, health equity, obesity and cancer, Cancer Causes & Control