MiR-125b appears to have a context-dependent dual role. Earlier in carcinogenesis, the review describes it mainly as a tumor suppressor, whereas therapeutic pressure can associate its activity with acquired chemoresistance. Regulation of apoptosis-related genes and pathways linked to cancer stem cell maintenance may help explain this shift. The findings indicate that the same microRNA can have opposing effects at different stages of breast cancer development, making its interpretation dependent on timing and biological setting rather than on expression alone.

The role of miR-375 is also strongly linked to breast cancer subtype. It is constitutively enriched in estrogen-receptor-positive luminal breast cancer, where reduced expression is associated with resistance to endocrine and anti-HER2 treatments. The review connects this pattern to dysregulation of the IGF1R, YAP1, JAK2/STAT3 and MTDH pathways. In triple-negative breast cancer, by contrast, miR-375 has a less clearly defined role and may participate in extracellular communication within the tumor microenvironment. The available evidence therefore supports different mechanistic interpretations across breast cancer categories rather than a single resistance model.

Lower miR-451 expression was associated in the reviewed studies with multidrug resistance involving MDR1/P-glycoprotein, Bcl-2 and YWHAZ signaling. Measurements in tissue and circulation did not necessarily move together, highlighting a possible role for extracellular vesicle trafficking in the distribution of the microRNA. The review also identifies hemolysis and other preanalytical variables as important influences on measured levels, emphasizing that laboratory procedures can affect the apparent signal. These observations nominate miR-451 as a subject for further validation but also caution against treating circulating measurements as interchangeable with tissue findings.

Collectively, the studies reviewed point to microRNAs as regulators of drug response through processes that include apoptosis, drug efflux, epithelial–mesenchymal transition, cancer stem cell maintenance and survival signaling. The three microRNAs do not form a uniform diagnostic panel: each is embedded in a different network, and their effects vary with tumor subtype, treatment pressure and sample context. Although miR-125b, miR-375 and miR-451 may eventually have value as biomarkers or therapeutic targets, the review emphasizes the need for standardized analytical methods, subtype-specific interpretation and prospective clinical validation. As a narrative synthesis rather than a new clinical trial, it maps the current evidence and identifies the gaps that remain before these potential applications can be assessed reliably.

Subject of Research: MicroRNA-mediated mechanisms of breast cancer chemoresistance

Article Title: Integrated roles of miR-125b, miR-375, and miR-451 in breast cancer chemoresistance: mechanistic insights and translational implications

Article References: Ahdi, D., Rashtchi, S., Hashemi, S., Khaniani, M. S., & Derakhshan, S. M. (2026). Integrated roles of miR-125b, miR-375, and miR-451 in breast cancer chemoresistance: mechanistic insights and translational implications. Molecular Biology Reports, 53(1), Article 1510. https://doi.org/10.1007/s11033-026-12426-1

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12426-1

Keywords: breast cancer, chemoresistance, miR-125b, miR-375, miR-451, microRNAs, drug resistance, cancer biomarkers, cancer stem cells, tumor microenvironment, Integrated, roles

The study, led by Abdallah Fallah, Alain Zgheib, Bogdan Alexandru Danalache, Nicoletta Eliopoulos and Borhane Annabi at the Université du Québec à Montréal and McGill University, used focused PCR arrays to compare U87 glioblastoma cells grown as conventional two-dimensional monolayers or as three-dimensional spheroids. The researchers then perturbed SORT1 in two ways: genetically, using SORT1-targeted siRNA (siSORT1), and pharmacologically, using AF38469, a Vps10p-domain antagonist that blocks the receptor’s ligand-binding arm. A non-targeting scrambled siRNA served as the genetic control.

The results reveal that when U87 cells are grown as 3D spheroids, they activate a coordinated transcriptional program that is largely absent in 2D monolayers. This program includes upregulation of angiogenic markers such as VEGFA and HIF1A, adipogenic and lipogenic regulators including PPARG, DDIT3, ADIPOQ, CEBPD and FOXO1, and a battery of glioblastoma stemness and drug-resistance markers including PROM1/CD133, SOX2, NANOG, CD44, ABCG2, ABCB5, TAZ and KITLG. Together, these changes indicate that 3D growth triggers a lipid-remodeling program with cancer stem cell features that are directly relevant to chemoresistance.

When the researchers silenced SORT1 or blocked it with AF38469, both interventions reduced spheroid size and repressed the adipogenic module, supporting a role for SORT1 in regulating adipogenesis and lipid-synthesis programs in glioblastoma spheroids. However, the two perturbations did not behave identically across the full transcriptional landscape. The cancer stem cell module proved far more sensitive to genetic SORT1 silencing, with 18 of 27 genes responding, than to pharmacological AF38469 treatment, which affected only 10 of 27 genes.

Among the transcripts that emerged as siSORT1-dependent but AF38469-insensitive were CXCL8, CD38, ZEB2, SOX2, NANOG and CD44. This bifurcation is significant because it suggests that SORT1 functions segregate into two arms: a ligand-dependent arm that AF38469 can target, and a ligand-independent, scaffold-like arm that requires SORT1 expression itself. The pharmacological inhibitor reproduces the genetic silencing effect nearly perfectly on the lipid and metabolic module but fails to do so on the developmental backbone of the cancer stem cell program.

Principal component analysis confirmed this dual-module organization. When siSORT1 and AF38469 were applied together, they jointly displaced the adipogenesis profile, whereas only siSORT1 clearly separated the cancer stem cell profile. This systems-level observation supports the idea that the bifurcation operates on entire transcriptional modules rather than on individual genes. The lipid and metabolism machinery plus drug-resistance elements form a co-regulated, ligand-dependent arm, while stemness, plasticity and the developmental backbone form a scaffold-dependent persistence arm.

The SORT1-dependent transcriptional state is organised into six functionally coherent modules, providing what the researchers describe as a modular blueprint for combinatorial therapeutic targeting. An AF38469 phenocopy index, a quantitative measure of how well the pharmacological inhibitor mimics genetic SORT1 silencing, provides strong support for this bifurcation model. The index shows that AF38469 reproduces the siSORT1 effect on the lipid and metabolic module but fails on the developmental backbone.

These findings are consistent with a model in which SORT1 behaves as a state-persistence node, associating adipogenic and lipogenic reprogramming with cancer stem cell-associated and drug-resistance-associated transcriptional programs. The researchers caution that this model remains to be tested with direct functional assays in 3D U87 spheroids, and the current study is primarily transcriptional in scope. Nevertheless, the modular organization offers a framework for designing combination strategies that could circumvent the acquired SORT1-regulated cancer stem cell and drug-resistance phenotype.

The broader implications are considerable. By creating hydrophobic compartments that sequester lipophilic chemotherapeutics, increased adipogenic reprogramming and lipid synthesis correlate with poor treatment response and increased drug tolerance in glioblastoma. SORT1 has been implicated in cancer stem cell biology and chemoresistance, and this study now provides a systems-level dissection of how the receptor links lipid remodeling to a chemoresistance-associated molecular signature. If the two-arm model holds up under direct functional testing, it could open new avenues for therapeutic intervention, combining AF38469-like ligand-dependent antagonists with strategies that target the scaffold-dependent arm of SORT1 biology.

The choice of a three-dimensional spheroid model deserves particular attention when weighing these results. Standard two-dimensional monolayer culture has long been criticized for stripping glioblastoma cells of the hypoxic, nutrient-gradient and cell–cell contact conditions that define the tumour microenvironment in patients. Hanging-drop spheroid systems restore some of these gradients, and it is precisely under these conditions that the adipogenic and stemness programs described here emerge. The fact that markers such as CD133 and SOX2 rise in spheroids relative to monolayers echoes a broader literature showing that 3D architecture alone, without any genetic manipulation, can push glioma cells toward a stem-like, therapy-tolerant state. This makes the spheroid platform a useful intermediate between simplified monolayers and animal models for probing drug-resistance biology.

The lipid dimension of the study connects to a growing appreciation of metabolic reprogramming in aggressive cancers. Lipid droplets act as hydrophobic sinks that can partition weakly lipophilic drugs away from their intracellular targets, effectively lowering the free drug concentration reaching the nucleus or microtubules. Enzymes of fatty acid synthesis and adipogenic transcription factors such as PPARG and CEBPD have each been independently linked to poor prognosis in high-grade gliomas. What the present work adds is a plausible coordinator: a single membrane receptor whose perturbation collapses much of this lipid program, suggesting that lipid remodeling in glioblastoma spheroids is not a diffuse set of parallel changes but a regulated module with an identifiable upstream node.

Sortilin itself has an unusual profile among trafficking receptors. It shuttles between the trans-Golgi network and endosomes, sorting cargo proteins involved in metabolism, inflammation and growth factor signaling. Its involvement in lipoprotein handling made it an attractive candidate when the authors sought a molecular bridge between lipid biology and cancer stem cell maintenance. The observation that a ligand-binding antagonist and a genetic knockdown diverge in their transcriptional consequences is consistent with a receptor that does more than transmit signals through ligand occupancy; it may also act as a physical scaffold, organizing protein complexes or cargo trafficking routes that persist as long as the protein is expressed, regardless of whether its ligand-binding pocket is occupied.

The specific transcripts that resist pharmacological blockade are informative. CXCL8, the gene encoding interleukin-8, is a chemokine associated with inflammatory recruitment, angiogenesis and stem cell maintenance in multiple tumour types. ZEB2 is a transcriptional repressor best known in epithelial–mesenchymal transition, but it also participates in developmental gene-regulatory networks in neural lineages. CD38, SOX2, NANOG and CD44 round out a set of markers tied to self-renewal and immune interaction. That these genes respond to loss of SORT1 expression but not to ligand-pocket antagonism implies that the scaffold-dependent arm of the receptor touches developmental and inflammatory programs that the ligand-dependent arm does not.

The drug-resistance markers in the spheroid signature also merit comment. ABCG2 and ABCB5 encode ATP-binding cassette transporters that actively pump structurally diverse chemotherapeutics out of cells, and both have been detected on glioblastoma stem-like populations. TAZ, a co-activator in the Hippo pathway, links mechanical cues from the 3D environment to transcriptional programs supporting proliferation and survival. The co-regulation of transporter genes with adipogenic regulators in a single module raises the possibility that lipid accumulation and drug efflux are not merely coincident but co-selected features of the same cellular state, which would explain why lipid-rich tumour cells so often prove chemoresistant.

Several caveats frame the interpretation. The work relies on a single cell line, U87-MG, which, although widely used, does not capture the molecular heterogeneity of patient glioblastomas, and the analysis is transcriptional rather than functional: no direct assays of spheroid viability under temozolomide challenge, stem cell frequency or lipid droplet burden are reported. Supplementary data on fibronectin distribution between cytosolic and nuclear fractions following SORT1 perturbation hint at downstream mechanistic threads, but these remain to be pulled. Validation across patient-derived glioblastoma stem cell cultures, organoids and in vivo models would be the natural next step.

If the two-arm model is confirmed, the therapeutic logic is straightforward but demanding. Blocking the ligand-dependent arm with AF38469-like molecules could deflate the lipid and metabolic machinery that shelters tumour cells from chemotherapy, while the scaffold-dependent arm would require entirely different approaches, such as degrading the receptor protein itself or disrupting its intracellular trafficking partners. The modular blueprint offered by this study, with its quantitative phenocopy index, gives medicinal chemists and translational researchers a measurable target profile for such combination strategies, and the open-access availability of the underlying datasets should facilitate independent evaluation of this provocative model.

Subject of Research: Sortilin-associated transcriptional programs in 3D glioblastoma spheroids

Article Title: A SORT1-associated transcriptional signature links adipogenic plasticity, stemness and drug-resistance programs in 3D glioblastoma spheroids: dissection of ligand-dependent and ligand-independent arms

Article References: Fallah, A., Zgheib, A., Danalache, B. A., Eliopoulos, N., & Annabi, B. (2026). A SORT1-associated transcriptional signature links adipogenic plasticity, stemness and drug-resistance programs in 3D glioblastoma spheroids: dissection of ligand-dependent and ligand-independent arms. BMC Cancer. https://doi.org/10.1186/s12885-026-16856-9

Image Credits: AI Generated

DOI: 10.1186/s12885-026-16856-9

Keywords: glioblastoma, SORT1, sortilin, cancer stem cells, 3D spheroids, chemoresistance, adipogenesis, AF38469, drug resistance, transcriptional modules, SORT1-associated, transcriptional

The review synthesizes mechanistic evidence across several protease families, including matrix metalloproteinases, cathepsins, ubiquitin-specific proteases, proteasome components, and mitochondrial proteases. Each family contributes to therapeutic escape through distinct routes. Matrix metalloproteinases, for example, remodel the extracellular matrix, physically altering the tumor microenvironment in ways that limit drug penetration and support invasion. Cathepsins, particularly cathepsin B, are highly expressed in pancreatic cancer stem-like cells and have been linked to poorer surgical outcomes, positioning them as both biomarkers and potential drug targets.

One of the most technically interesting threads involves ubiquitin-specific proteases, enzymes that remove ubiquitin tags from proteins and thereby rescue them from degradation. By stabilizing pro-survival proteins, these deubiquitinases can blunt the effect of drugs that rely on triggering apoptotic pathways. Ubiquitin-specific protease 7 has attracted particular attention as a target for overcoming drug resistance, and inhibitors of these enzymes are being explored as a route to re-sensitize tumors that have learned to survive chemotherapy.

The proteasome itself, the cellular machine that degrades tagged proteins, represents another protease-centered axis of resistance. Proteasome inhibitors such as bortezomib, carfilzomib, and ixazomib have already achieved clinical success, most notably in multiple myeloma, where the phase 3 ENDEAVOR trial demonstrated the benefit of carfilzomib combined with dexamethasone over bortezomib-based therapy. These agents prove that protease-directed therapy can work in the clinic, even if their greatest successes have come in hematological malignancies rather than solid tumors.

Perhaps the most striking clinical story involves HIV protease inhibitors, drugs originally designed for a completely different disease. Nelfinavir, saquinavir, ritonavir, lopinavir, and indinavir have all shown anticancer activity in various settings. Nelfinavir inhibits proteasome function and induces endoplasmic reticulum stress in glioma cells, while ritonavir suppresses survivin in lung cancer cells. Clinical trials have tested nelfinavir alongside chemoradiation in locally advanced pancreatic cancer, from early phase 1 studies through the phase 2 ARCII trial and the more recent SCALOP-2 trial, and a phase 3 protocol known as NELCER is evaluating nelfinavir with chemoradiation and brachytherapy in cervical cancer. A phase 2 trial also reported clinical efficacy of indinavir combined with chemotherapy for advanced classic Kaposi sarcoma in elderly patients.

Why, then, has broad-spectrum protease inhibition largely disappointed in oncology? The review identifies several converging reasons. Many inhibitors lack sufficient isoform selectivity, hitting multiple protease family members with different, sometimes opposing, roles. Cancer cells compensate through parallel signaling pathways, so blocking one route of resistance simply reroutes the traffic. Patient stratification has often proceeded without biomarkers that identify who actually carries the relevant protease dependency, and pharmacodynamic validation, confirming that the drug truly engaged its target in the tumor, has frequently been missing. The result is a persistent gap between strong biological rationale and limited clinical success.

The mechanistic landscape is further complicated by the interplay between proteases and other hallmarks of resistance. Proteases regulate epithelial-mesenchymal transition, the program by which cancer cells become more invasive and drug-tolerant, and they help maintain cancer stem cell populations that seed relapse. They also intersect with signaling cascades such as PI3K/AKT/NF-κB and MAPK pathways, with oxidative stress responses, and with autophagy, all of which have been implicated in resistance to agents ranging from gemcitabine and doxorubicin to platinum drugs and taxanes. Targeting a single enzyme family without accounting for this network risks repeating the failures of earlier broad-spectrum matrix metalloproteinase inhibitors, such as marimastat, which showed no benefit in a randomized trial of glioblastoma patients.

Emerging strategies aim to escape this trap by being context-specific rather than indiscriminate. Biomarker-guided patient selection seeks to treat only those tumors whose proteomic profiles reveal genuine protease dependencies. Rational combination therapy pairs protease inhibitors with conventional chemotherapeutics in ways suggested by systematic drug combination screens, such as the large-scale effort published in Nature that mapped effective combinations in breast, colon, and pancreatic cancer cell lines. Advanced delivery platforms add another layer of precision: protease-activated prodrugs release their payload only where specific proteases are active, and nanoparticle systems, including matrix metalloproteinase-responsive nanoparticles and thermosensitive liposomes carrying MMP inhibitors, concentrate inhibitory activity within the tumor microenvironment while sparing healthy tissue.

The review also highlights tools that could sharpen the field’s aim. Proteomic profiling, integrated with functional validation, may identify which proteases a given tumor truly depends upon, moving treatment decisions from empirical enzyme blockade toward mechanism-driven intervention. Activity-based probes, already evaluated preclinically for intraoperative imaging of esophageal cancer, exemplify how protease activity can be visualized directly, potentially guiding both diagnosis and surgical margins. Natural product-derived inhibitors, such as the Bowman-Birk family of protease inhibitors, continue to be explored as sources of multifunctional lead compounds.

Kurian’s synthesis ultimately delivers a measured but forward-looking message. Proteases are deeply woven into the machinery of chemoresistance, modulating drug transport, extracellular matrix remodeling, epithelial-mesenchymal transition, apoptosis, and pro-survival signaling across multiple malignancies. The clinical record shows both the promise of the approach, through proteasome inhibitors and repurposed HIV protease inhibitors, and its pitfalls, through failed broad-spectrum trials. The path forward, the review argues, lies in precision: matching the right protease target to the right tumor, validated by biomarkers and delivered by smart drug platforms. Whether that precision can be achieved at scale remains the decisive question, and the author is careful to note that further clinical validation is still required before protease inhibition can fulfill its promise of breaking the barriers of chemoresistance in cancer.

Subject of Research: The role of protease families in cancer chemoresistance and strategies for protease-targeted therapy

Article Title: Protease inhibition: breaking the barriers of chemoresistance in cancer

Article References: Kurian, G. A. (2026). Protease inhibition: breaking the barriers of chemoresistance in cancer. Molecular Biology Reports, 53(1), Article 1548. https://doi.org/10.1007/s11033-026-12659-0

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12659-0

Keywords: chemoresistance, proteases, matrix metalloproteinases, cathepsins, ubiquitin-specific proteases, proteasome inhibitors, HIV protease inhibitors, tumor microenvironment, biomarker-guided therapy, nanoparticle drug delivery, cancer stem cells, nelfinavir

The stakes of getting this call right could hardly be higher. The standard escalation for high-risk pediatric AML is stem cell transplantation in first remission, a procedure that replaces a child’s blood-forming system with that of a donor. Transplantation carries substantial toxicity, including the risk of graft-versus-host disease, in which donor immune cells attack the recipient’s own tissues, and it imposes a heavy burden on children who may not actually need it. At the same time, cures after relapse are rare, so under-treating a child who is destined to relapse can be a fatal error. The clinical dilemma is therefore a razor’s edge: overtreat and harm children unnecessarily, or undertreat and lose those who needed the transplant. Accurate risk prediction is the instrument that determines which side of the edge each child falls on.

The research team, co-led by Mohammad Javad NajafPanah, Alexandra M. Stevens, and Tsz-Kwong Man, with senior authorship from Michele S. Redell and Pavel Sumazin, attacked the problem with single-cell transcriptomics, a technology that reads out the gene activity of individual cells rather than averaging signals across a bulk tumor sample. Bulk measurements have a well-known blind spot: a population of cells that makes up even a few percent of a sample can carry decisive biological information, yet its signature is diluted beyond recognition in the aggregate. By profiling cells one at a time, the researchers could compare the transcriptomic landscapes of paired samples taken at diagnosis and at relapse, and infer which cell populations present at diagnosis had the molecular characteristics of cells that survived chemotherapy and reseeded the disease.

This pairing of diagnosis and relapse samples is the methodological heart of the study. When a leukemia relapses, the cells driving it are, by definition, the chemoresistant survivors of the original clone. By identifying transcriptional programs shared between specific cell populations at diagnosis and the relapse population that later emerged, the team could define a chemoresistant signature detectable in the very first sample drawn from a patient. The approach converts relapse, which clinicians usually experience as a retrospective catastrophe, into a prospective signal: the biology of treatment failure is written into the diagnostic sample, and single-cell analysis provides the lens needed to read it.

But the researchers did not stop at the single-cell signature. Their risk model integrates three independent layers of information: the presence of chemoresistant cell populations inferred from single-cell transcriptomic profiles, cytogenetic biomarkers measured at diagnosis, and measurable residual disease, or MRD, assessed after induction chemotherapy. Cytogenetics, the chromosomal abnormalities visible in leukemic cells, has been a cornerstone of AML risk classification for decades. MRD, detected by flow cytometry or molecular assays, measures the burden of leukemic cells remaining after the first round of treatment and is among the strongest known predictors of relapse. Each of these tools, used alone, leaves a fraction of patients misclassified. The insight of the new work is that the three layers are complementary, capturing different facets of the disease, and that combining them yields a risk prediction substantially better than any component alone.

The clinical payoff is striking. Applying the combined approach, the team identified a patient subgroup comprising roughly twenty percent of children with pediatric AML who, under current risk criteria, do not undergo stem cell transplantation in first remission. Within this subgroup, five-year event-free survival fell below forty percent, and these patients accounted for nearly half of all deaths in the non-transplanted population. In plain terms, the model found a hidden cohort of children who look low-risk by conventional measures but who carry a prognosis comparable to the highest-risk groups, and who are precisely the patients for whom the toxicity of transplantation might be justified. For a disease in which relapse is so often fatal, flagging one in five patients who would otherwise be missed represents a meaningful shift in the risk landscape.

Equally important is what the molecular characterization of the chemoresistant populations revealed about therapeutic vulnerabilities. By defining the transcriptional programs that allow cells to survive chemotherapy, the study points toward targeted treatment strategies that could be deployed against those programs directly. The authors frame this as a framework for precision oncology in pediatric AML: diagnosis that incorporates single-cell inference of chemoresistance, risk stratification that integrates that inference with established biomarkers, and intervention guided by the specific molecular dependencies of the resistant cells. While the study does not yet translate into a bedside therapy, it provides a mechanistically grounded map of where such therapies should aim.

The study draws on data generated by the TARGET initiative, managed by the National Cancer Institute and available through the Genomic Data Commons, reflecting the growing importance of large, shared pediatric cancer datasets in enabling this kind of computational analysis. The work was supported by a broad coalition of funders, including the Cancer Prevention and Research Institute of Texas, the National Institutes of Health, the St. Baldrick’s Foundation, and Wipe Out Kids’ Cancer, among others. The collaboration spanned institutions on both sides of the Atlantic, with contributions from Yale School of Medicine, the University of Lausanne, and the University of Zurich, a reminder that modern precision oncology is as much a data-science enterprise as a clinical one.

For the field, the significance of the study lies less in any single number than in a change of perspective. Risk stratification in pediatric AML has historically relied on what the disease looks like, its chromosomal abnormalities and its response to the first round of chemotherapy. The new work adds a question that could only be answered at single-cell resolution: what is the disease capable of surviving? By reading the chemoresistant potential of a leukemia directly from its diagnostic transcriptome, clinicians may one day know, at the moment of diagnosis, which children’s disease will endure, and can plan transplantation, targeted agents, or intensified therapy accordingly. For the roughly one in five children the model rescues from misclassification, and for the families who currently learn of relapse only when it is too late to change course, that knowledge may prove to be the difference between a treatment plan and a gamble.

Considerable work remains before single-cell risk profiling becomes standard of care. The technology is expensive, the computational pipelines demand specialized expertise, and prospective clinical validation will be needed to confirm that acting on the new risk categories improves outcomes. Yet the trajectory of the field is clear. The study demonstrates that the information required to predict relapse is present from the outset, encoded in the transcriptional state of a minority population of cells, and that combining that information with cytogenetics and MRD produces a stratification powerful enough to change transplant decisions. In a disease where nearly half of deaths among non-transplanted children concentrate in a group that current criteria label as lower risk, the ability to see those cells coming is not an incremental advance. It is the kind of reframing that precision oncology has promised for years, delivered for one of the hardest cancers in pediatric medicine.

Subject of Research: Chemoresistant cell populations and risk stratification in pediatric acute myeloid leukemia

Article Title: Characterization of chemoresistant cell populations improves risk stratification and therapy prediction in pediatric acute myeloid leukemia

Article References: NajafPanah, M. J., Stevens, A. M., Krueger, M. J., Rochette, M., Sandhu, S., Kim, L., Chiu, H.-S., Epps, J., Somvanshi, S., Zorman, B., Rodriguez Martinez, M., Rapsomaniki, M., Unger, S., Becher, B., Yi, J. S., Man, T.-K., Redell, M. S., & Sumazin, P. (2026). Characterization of chemoresistant cell populations improves risk stratification and therapy prediction in pediatric acute myeloid leukemia. Nature Communications. https://doi.org/10.1038/s41467-026-78283-5

Image Credits: AI Generated

DOI: 10.1038/s41467-026-78283-5

Keywords: pediatric acute myeloid leukemia, single-cell transcriptomics, chemoresistance, risk stratification, measurable residual disease, stem cell transplantation, cytogenetics, relapse prediction, precision oncology, Nature Communications, childhood cancer, Texas Children's Cancer Center

The review, led by researchers from Ahmadu Bello University, Adeleke University, Babcock University, and collaborating Nigerian institutions, synthesizes preclinical, epidemiological, and emerging clinical evidence for six structurally distinct classes of plant-derived compounds: alkaloids, flavonoids, terpenoids, polyphenols, coumarins, and organosulfur compounds. These phytochemicals modulate multiple oncogenic pathways relevant to gynecological malignancies, including tumor cell proliferation, intrinsic and extrinsic apoptosis, angiogenesis, oxidative stress, inflammation, hormone receptor signaling, HPV E6/E7 oncoprotein expression, and epigenetic regulation. The authors argue that the breadth of mechanistic activity—rather than a single molecular target—distinguishes plant-derived interventions from many conventional cytotoxic agents and may explain their potential to complement standard therapies.

Paclitaxel, a taxane terpenoid isolated from the bark of Taxus brevifolia, serves as the definitive proof of concept that plant-derived compounds can achieve gold-standard clinical status in gynecological oncology. Paclitaxel stabilizes polymerized microtubules, arrests dividing cells in G2/M phase, and phosphorylates Bcl-2 to trigger apoptosis. In combination with carboplatin, it is the standard of care worldwide for advanced ovarian cancer, with a reported five-year overall survival of approximately 45 percent. Topotecan, a semi-synthetic derivative of the alkaloid camptothecin, inhibits topoisomerase I and holds regulatory approval for platinum-resistant recurrent ovarian cancer and advanced cervical cancer, based on data from Phase II/III trials including the GOG-179 study. Vincristine and vinblastine, derived from Catharanthus roseus, arrest ovarian and cervical cancer cells through beta-tubulin binding, though dose-limiting neurotoxicity restricts their use as single agents.

Among non-approved phytochemicals, the review highlights several with compelling preclinical activity. Berberine, a protoberberine alkaloid from Berberis vulgaris, inhibits proliferation and promotes apoptosis in Ishikawa endometrial carcinoma cells through modulation of PI3K/AKT signaling, with concurrent AMPK activation and NF-κB inhibition. Quercetin induces mitochondrial membrane depolarization, cytochrome c release, and caspase-3/9 activation in SKOV-3 and A2780 ovarian cancer cells while suppressing VEGF transcription in HeLa cervical cancer cells. Apigenin induces caspase-dependent apoptosis and PARP cleavage in HeLa cells and, distinctively, suppresses HPV E6/E7 oncoprotein expression—targeting the viral driver of cervical carcinogenesis rather than only downstream oncogenic effects. Kaempferol inhibits STAT3 phosphorylation and restores p53 function in cisplatin-resistant ovarian cancer cells, a mechanistically important observation given that constitutive STAT3 activation is a well-characterized driver of platinum resistance.

Polyphenols such as curcumin, resveratrol, and epigallocatechin-3-gallate (EGCG) show particular promise. Curcumin suppresses NF-κB, AP-1, and COX-2, shifts Bax/Bcl-2 ratios toward apoptosis, and downregulates HPV E6 and E7 in cervical cancer cell lines. In combination with tanshinone IIA, curcumin inhibits HPV-positive W12 cervical precancer cells at sub-IC50 doses of each agent alone. Resveratrol activates SIRT1 and inhibits PI3K/AKT/mTOR signaling, restoring taxane sensitivity in paclitaxel-resistant ovarian cancer cell lines. EGCG inhibits DNMT1, DNMT3a, and DNMT3b, reactivating silenced tumor suppressor genes through epigenetic reprogramming. The strongest clinical signal among non-approved compounds comes from EGCG in cervical precancer: a Phase II randomized trial reported 69 percent histologically confirmed regression of CIN 2/3 lesions with oral and topical EGCG at 200 mg per day, compared with 10 percent in placebo controls.

Hormone receptor modulation represents another mechanistic frontier. Soy-derived isoflavones genistein and daidzein bind estrogen receptor beta with higher affinity than estrogen receptor alpha, opposing ER-alpha-mediated proliferative signaling in the endometrium. In mice, dietary genistein and daidzein significantly reduced the incidence of endometrial adenocarcinoma and atypical hyperplasia. A meta-analysis of ten observational studies reported a 49 percent reduction in ovarian cancer risk with higher phytoestrogen intake (RR 0.51, 95% CI 0.38–0.69). The authors caution, however, that the net estrogenic or anti-estrogenic effect of phytoestrogens depends on ambient estrogen levels, receptor subtype ratios, and cancer molecular subtype, producing conflicting results across different in vitro systems that must inform patient stratification in future trials.

Coumarins and organosulfur compounds round out the mechanistic landscape. Auraptene and scopoletin exert anti-invasive and anti-proliferative effects in ovarian and endometrial cancer cells through combined inhibition of PI3K/AKT/mTOR signaling and matrix metalloproteinase activity. Importantly, coumarin derivatives demonstrate the capacity to reverse P-glycoprotein-mediated multidrug resistance—a critical contributor to platinum and taxane resistance in ovarian cancer—through direct P-gp inhibition. Allicin and related organosulfur compounds from garlic induce apoptosis in ovarian and endometrial cancer cells through ROS generation, Nrf2 pathway activation, and Bax/Bcl-2 ratio modulation, with anti-migratory effects documented through suppression of MMP-2 and MMP-9 gelatinase activity.

Poor oral bioavailability remains the most significant obstacle to clinical translation for most non-approved phytochemicals. Curcumin has oral bioavailability below 1 percent in unformulated form due to rapid intestinal and hepatic phase II metabolism, primarily glucuronidation and sulfation. EGCG undergoes catechol-O-methyltransferase-mediated methylation, substantially reducing systemic stability. Resveratrol exhibits rapid first-pass metabolism with a plasma half-life ranging from minutes to low hours. Nanoformulation strategies directly address these limitations: liposomal encapsulation improves aqueous solubility and protects compounds from presystemic metabolism, PLGA biodegradable nanoparticles provide sustained drug release, and phytosomes enhance membrane permeability. Co-administration of piperine inhibits intestinal glucuronidation and modulates efflux transporters, resulting in approximately 20-fold increases in curcumin area under the curve in human volunteer studies. Nab-paclitaxel, an albumin-bound nanoparticle formulation of paclitaxel, provides a clinically validated regulatory precedent for nanoformulated phytochemical therapeutics.

The review identifies critical barriers limiting clinical translation: botanical preparations are unstandardized, randomized trial data in gynecological cancer populations are scarce, and herb-drug interaction profiles are incompletely characterized. EGCG inhibits CYP3A4 and CYP2C9 enzymes affecting paclitaxel, cyclophosphamide, and tamoxifen metabolism; piperine broadly inhibits P-gp and other CYP isoforms, potentially increasing plasma levels of co-administered chemotherapy. High-dose isoflavone supplementation in women taking hormonal therapy for ER-positive endometrial or ovarian cancer is not currently supported by evidence. The authors call for biomarker-embedded Phase II randomized trials with pharmacokinetic sampling, molecular subtype-stratified patient selection, and rigorous evaluation of phytochemical-chemotherapy combination regimens. Precision medicine strategies—such as identifying KEAP1/NRF2-mutant ovarian tumors responsive to phytochemical-mediated oxidative stress modulators, or high-DNMT1 cervical cancers sensitive to epigenetic reprogramming—could significantly enhance the signal-to-noise ratio of future clinical trials.

Subject of Research: Health & Medicine

Article Title: Impact of plant-based interventions on gynecological cancers: a narrative review of mechanistic interplays and clinical evidence

Article References: Fabrael, F. B., Sotunsa, J., Olaniyi, K. S., Oghenetega, O. B., Adewale, O., Akindele, B. M., Olanrewaju, F., Gbimadee, N. L., Olayemi, S., Bolaji, A. O., Iyobhebhe, M. O., Adegbotoluwa, E. M., Folahanmi, E. D., Kaisar, J. A., & Oyedokun, P. A. (2026). Impact of plant-based interventions on gynecological cancers: a narrative review of mechanistic interplays and clinical evidence. Frontiers in Molecular Medicine, 6, Article 1832188. https://doi.org/10.3389/fmmed.2026.1832188

Image Credits: AI Generated

DOI: 10.3389/fmmed.2026.1832188

Keywords: gynecological cancers, phytochemicals, paclitaxel, curcumin, EGCG, HPV, nanoformulation, chemoresistance, Frontiers in Molecular Medicine, Impact, plant-based, interventions

Epithelial ovarian carcinoma is the most common form of ovarian cancer and is frequently diagnosed at an advanced stage, when the disease has already spread within the abdominal cavity. Although initial responses to platinum-based chemotherapy are often encouraging, many patients eventually relapse with tumors that no longer respond to the same drugs. Understanding the molecular mechanisms that drive this chemoresistance is therefore a central goal in ovarian cancer research, and microRNAs have emerged as important players in that landscape.

MicroRNAs are short, non-coding RNA molecules, typically around 21 to 24 nucleotides long, that regulate gene expression after a gene has been transcribed into messenger RNA. Each microRNA can bind to complementary sequences in target messenger RNAs, blocking their translation into protein or triggering their degradation. Because a single microRNA can regulate multiple genes within a pathway, these molecules act as fine-tuning switches for cellular behavior, and their dysregulation is well documented in many cancers, including epithelial ovarian carcinoma.

To investigate whether microRNAs contribute to the control of collagen type IV alpha 6, a protein known as COL4A6 that is overexpressed in ovarian cancer and linked to tumor progression, chemoresistance, and poor clinical outcomes, the researchers measured levels of microRNA-197-3p in ovarian cancer tissues and cell lines using real-time polymerase chain reaction. They found that the microRNA was markedly reduced in both tumor samples and laboratory-grown ovarian cancer cells compared with non-cancerous controls, suggesting that the loss of this regulatory molecule may be a common feature of the disease.

The team then carried out functional experiments to determine what happens when microRNA-197-3p is restored in cancer cells. Using assays that measure cell viability and responsiveness to cisplatin, they showed that increasing the microRNA suppressed the survival of ovarian cancer cells and made them more sensitive to the chemotherapy drug. Conversely, reducing the microRNA had the opposite effect, supporting the idea that this molecule acts as a brake on both tumor growth and drug resistance.

Mechanistic studies provided the crucial link between the microRNA and its target. Through luciferase reporter testing, a technique in which scientists fuse a suspected target sequence to a light-producing enzyme to see whether a microRNA can dampen its output, the researchers demonstrated that microRNA-197-3p directly targets COL4A6. Western blotting, which detects specific proteins in cell extracts, confirmed that manipulating the microRNA changed the amount of COL4A6 protein produced by the cells. When the researchers altered this regulatory axis, either by changing microRNA levels or by manipulating COL4A6 itself, cellular survival and chemoresistance shifted accordingly.

The clinical significance of the finding emerged when the team examined associations between microRNA-197-3p expression and patient outcomes. In univariate analyses, diminished levels of the microRNA correlated with more advanced disease stage, poorer response to chemotherapy, recurrence of the disease, and reduced survival. These associations suggest that measuring microRNA-197-3p could potentially serve as a biomarker for identifying patients at higher risk of treatment failure, although the researchers note that further validation in larger cohorts would be needed before such a test could enter clinical practice.

The study also sheds light on why COL4A6 matters in ovarian cancer biology. Collagen type IV is a structural component of the basement membrane, the thin layer of extracellular matrix that underlies epithelial tissues, and the alpha 6 chain encoded by COL4A6 has been implicated in how cancer cells interact with their surroundings. By suppressing COL4A6, microRNA-197-3p appears to interfere with molecular programs that support tumor progression and resistance to cell death triggered by chemotherapy. The researchers conclude that microRNA-197-3p inhibits epithelial ovarian carcinoma progression and reduces chemoresistance by directly targeting COL4A6, underscoring its promise as a potential therapeutic candidate.

Translating this laboratory finding into a clinical therapy remains a considerable challenge. Delivering microRNA molecules into tumor cells in patients requires safe and effective delivery vehicles, and microRNA-based therapeutics are still an emerging area of oncology. Nevertheless, the identification of a specific microRNA-target pair that governs both tumor growth and platinum drug sensitivity offers a clear molecular target for future drug development. If subsequent studies confirm the role of the microRNA-197-3p and COL4A6 axis in larger patient populations and in animal models, it could open the door to combination strategies in which microRNA restoration is paired with existing chemotherapy to overcome resistance in ovarian cancer.

Subject of Research: The role of microRNA-197-3p in targeting collagen type IV alpha 6 to overcome chemoresistance in epithelial ovarian carcinoma

Article Title: MicroRNA-197-3p counteracts chemoresistance in ovarian cancer via collagen type IV alpha 6 inhibition

Article References: Wu, Y.-H., Wu, P.-Y., Chang, T.-H., Huang, Y.-F., Hsieh, T.-Y., & Chou, C.-Y. (2026). MicroRNA-197-3p counteracts chemoresistance in ovarian cancer via collagen type IV alpha 6 inhibition. Journal of Ovarian Research. https://doi.org/10.1186/s13048-026-02295-4

Image Credits: AI Generated

DOI: 10.1186/s13048-026-02295-4

Keywords: ovarian cancer, microRNA-197-3p, COL4A6, chemoresistance, cisplatin, epithelial ovarian carcinoma, gene regulation, oncology, biomarker, microRNA therapeutics, tumor progression, Journal of Ovarian Research

Under normal physiological conditions, the bone marrow niche maintains hematopoietic stem and progenitor cells in a delicate balance of quiescence, self-renewal, and differentiation. This balance is orchestrated through tightly regulated interactions among cytokines, chemokines, adhesion molecules, and metabolic cues. In AML, however, leukemic cells disrupt this equilibrium by secreting their own signals and by directly reprogramming stromal, vascular, immune, and metabolic components of the niche. The result is a microenvironment that no longer supports healthy blood production but instead favors malignant persistence. The review emphasizes that this reprogramming is not a passive consequence of tumor growth but an active, bidirectional crosstalk driven by soluble factors, cell-to-cell contact, extracellular vesicles, and metabolic exchange.

At the heart of this crosstalk lies the CXCL12–CXCR4 chemokine signaling axis, described by the authors as the dominant regulatory pathway governing leukemic cell homing and retention. CXCL12, also known as stromal-derived factor-1, is continuously secreted by mesenchymal stromal cells, osteoblasts, and endothelial cells within the bone marrow. AML blasts frequently overexpress CXCR4, the receptor for CXCL12, allowing them to respond strongly to this gradient and anchor themselves within protective niches. Upon activation, CXCR4 triggers intracellular cascades including PI3K/AKT, ERK/MAPK, and NF-κB, which collectively promote survival, proliferation, and resistance to apoptosis. Clinically, high CXCR4 expression correlates with poor prognosis and increased relapse risk, underscoring the pathway’s central role in disease progression.

Beyond chemokines, the review details how cytokines and growth factors shape the leukemic niche. Transforming growth factor-beta (TGF-β), produced by stromal cells, immune cells, and sometimes by leukemic blasts themselves, activates SMAD-dependent transcriptional programs that suppress immune cell function and drive leukemic cells toward a quiescent state less vulnerable to cell cycle–dependent chemotherapy. Vascular endothelial growth factor (VEGF) promotes angiogenesis and vascular remodeling, creating specialized microenvironments rich in growth factors and oxygen gradients that sustain leukemic stem cells. Inflammatory cytokines such as TNF-α and interleukin-6 activate NF-κB and JAK/STAT signaling respectively, reinforcing anti-apoptotic gene expression and creating a feed-forward loop that sustains both niche remodeling and leukemic persistence.

The review also highlights the emerging role of extracellular vesicles, particularly exosomes ranging from 30 to 150 nanometers, as key mediators of intercellular communication in AML. Leukemic cells release large numbers of these membrane-bound vesicles, which are taken up by stromal, endothelial, and immune cells through endocytosis or membrane fusion. The cargo—proteins, lipids, and microRNAs such as miR-155 and miR-150—alters gene expression in recipient cells, converting healthy mesenchymal stromal cells into leukemia-supportive elements that secrete increased amounts of IL-6, IL-8, and CCL2. This bidirectional reprogramming establishes a self-reinforcing inflammatory loop that enhances leukemic retention, survival, and chemoresistance. Extracellular vesicles also suppress T-cell proliferation and natural killer cell cytotoxicity, extending the immunosuppressive reach of the leukemic niche beyond the bone marrow itself.

Adhesion-mediated signaling represents another critical layer of chemoprotection. Integrins such as VLA-4 on leukemic cells bind to VCAM-1 on stromal cells, triggering PI3K/AKT signaling that enhances anti-apoptotic responses and reduces chemotherapy sensitivity. β2-integrins activate a Syk–STAT signaling axis that further boosts leukemic survival and proliferation. This phenomenon, termed cell adhesion–mediated drug resistance (CAM-DR), allows AML cells to physically anchor themselves within niches that shield them from cytotoxic agents while simultaneously activating intracellular survival pathways. The review notes that stromal niches can also provide a physical barrier, allowing residual leukemic stem cells to survive treatment and eventually seed relapse.

Metabolic crosstalk between leukemic cells and the bone marrow microenvironment adds yet another dimension to niche-mediated chemoprotection. Bone marrow adipocytes supply fatty acids that leukemic cells utilize through fatty acid oxidation, enhancing mitochondrial function and providing an alternative energy source under nutrient stress. Stromal cells contribute amino acids and lipids that sustain biosynthetic activity. Hypoxic regions within the leukemic marrow stabilize hypoxia-inducible factors HIF-1α and HIF-2α, driving metabolic reprogramming toward glycolysis and upregulating angiogenic factors such as VEGF. Cells in these hypoxic niches often show reduced sensitivity to chemotherapy, partly due to slower growth and activation of HIF-dependent anti-apoptotic pathways. The authors emphasize that these metabolic adaptations are not isolated events but converge on shared intracellular hubs including PI3K/AKT and mTOR signaling.

The immune microenvironment within the AML bone marrow undergoes profound functional impairment. T cells exhibit signs of exhaustion marked by reduced proliferation and impaired cytokine production, driven in part by activation of the PD-1/PD-L1 immune checkpoint axis. Regulatory T cells are often expanded, further suppressing anti-leukemic responses through TGF-β–mediated mechanisms. Natural killer cells, which normally target and destroy malignant cells, are inhibited by TGF-β signaling that reduces expression of activating receptors and cytotoxic mediators. Macrophages within the leukemic niche acquire tumor-associated phenotypes, secreting IL-6, TNF-α, and IL-10 to reinforce survival signaling and immune suppression. Myeloid-derived suppressor cells further block T-cell activation through reactive oxygen species and immunosuppressive cytokines. Galectins, particularly galectin-1, galectin-3, and galectin-9, contribute additional layers of immune modulation and drug resistance.

A particularly important insight from the review concerns the spatial organization of leukemic stem cells within distinct bone marrow niches. The endosteal niche, composed of mesenchymal stromal cells, osteoblastic cells, and extracellular matrix components, maintains leukemic stem cells in a quiescent G0 state through signals that limit cell cycle entry. This

Subject of Research: Bone marrow niche-mediated chemoprotection and chemoresistance mechanisms in acute myeloid leukemia

Article Title: Crosstalk of factors underlying bone marrow niche-mediated chemoprotection in acute myeloid leukemia

Article References: Shah, A., Trivedi, A. K., & Chaturvedi, C. P. (2026). Crosstalk of factors underlying bone marrow niche-mediated chemoprotection in acute myeloid leukemia. Frontiers in Hematology, 5, Article 1850831. https://doi.org/10.3389/frhem.2026.1850831

Image Credits: AI Generated

DOI: 10.3389/frhem.2026.1850831

Keywords: acute myeloid leukemia, bone marrow niche, chemoresistance, CXCL12-CXCR4, leukemic stem cells, tumor microenvironment, extracellular vesicles, Frontiers in Hematology, Crosstalk, factors, underlying, bone

Acute myeloid leukaemia is a highly heterogeneous blood cancer driven by the clonal expansion of immature myeloid cells, and long-term survival remains poor. Many patients achieve complete remission after standard induction chemotherapy with cytarabine and an anthracycline, yet the majority eventually relapse because the disease acquires drug resistance. Mounting evidence points to the bone marrow microenvironment as a central accomplice in this process. The new study, led by researchers at Fujian Medical University Union Hospital, focused on bone marrow stromal cells and asked precisely how these cells confer a survival advantage on leukaemic blasts under therapeutic stress.

The starting clue came from the team’s own earlier work showing that AML cells grown alongside stromal cells ramp up mitochondrial oxidative phosphorylation, the energy-generating process that leukaemic cells rely on heavily to meet their bioenergetic and biosynthetic demands. Elevated mitochondrial respiration, however, comes at a cost: it produces more reactive oxygen species, particularly within the mitochondria. Excessive mitochondrial ROS can trigger dysfunction and apoptosis, but a moderate increase can paradoxically activate adaptive antioxidant responses that enhance cell survival, a phenomenon known as mitohormesis. In the new experiments, AML cells co-cultured with stromal cells showed significantly higher intracellular ROS levels, yet their viability was unchanged, implying that compensatory antioxidant defences had been induced. Those cells displayed greater total antioxidant activity and increased tolerance to hydrogen peroxide, and the same pattern appeared in primary AML cells taken from patients.

To test whether antioxidant capacity was truly the determinant of chemoresistance, the researchers manipulated it chemically. N-acetyl-L-cysteine, a precursor of glutathione, the cell’s principal antioxidant molecule, mimicked the stromal effect by enhancing antioxidant activity and drug resistance. Conversely, 2-phenylethyl isothiocyanate, which depletes glutathione, abolished antioxidant function and sensitized AML cells to both oxidative stress and chemotherapy. These results established that stromal cells enhance the antioxidant capacity of leukaemic cells, thereby conferring resistance to oxidative damage and cytotoxic drugs.

The next question was which upstream signal mediates this adaptation. Because mitochondrial ATP production was known to rise in AML cells co-cultured with stromal cells, the team turned to purinergic receptors, sensors of extracellular nucleotides that regulate tumour cell survival, metabolism and therapy response. Their attention settled on P2RX7, a ligand-gated ion channel on the plasma membrane activated by extracellular ATP. P2RX7 is highly expressed in leukaemic blasts and leukaemia-initiating cells, and its elevated expression correlates with poor clinical outcomes. Functionally, it has been implicated in promoting leukaemic cell survival, proliferation and homing to the bone marrow niche. In the new study, P2RX7 protein was markedly upregulated in AML cells co-cultured with stromal cells, and the same upregulation appeared when primary AML cells were grown with mesenchymal stromal cells extracted from AML patients themselves.

Functionally, the picture was equally clear. Treating AML cells with BzATP, a P2RX7 agonist, reduced their sensitivity to cytarabine and daunorubicin, while the selective antagonist AZ10606120 blocked that effect and partially reversed the protection conferred by stromal co-culture. Using CRISPR/Cas9-mediated knockout and lentiviral overexpression, the researchers confirmed the causal role: genetic ablation of P2RX7 impaired both antioxidant capacity and chemoresistance, effects that could be rescued by glutathione supplementation, whereas overexpression enhanced both, an effect abolished by glutathione depletion. To directly link P2RX7-mediated antioxidant defence to protection against oxidative damage, the team measured 8-hydroxy-2′-deoxyguanosine, a marker of oxidative DNA damage. Cytarabine increased 8-OHdG levels, and this effect was further augmented in P2RX7-deficient cells. Co-culture with stromal cells failed to reduce 8-OHdG accumulation in P2RX7-null cells, indicating that stromal support is insufficient to compensate for P2RX7 loss. Overexpressing cells, in contrast, displayed reduced 8-OHdG levels after drug exposure.

The mechanistic core of the study concerns how P2RX7 imposes mitochondrial stress that ultimately licences a robust antioxidant programme. As a calcium-permeable channel, P2RX7 activation promotes cytosolic calcium influx, sodium influx and potassium efflux. Using the calcium chelator BAPTA-AM, the researchers showed that reducing cytosolic calcium decreased both mitochondrial calcium uptake and mitochondrial ROS levels. Pharmacological inhibitors of mitochondrial calcium uptake, SN-6 and Ru360, suppressed mitochondrial calcium loading and ROS, whereas CGP37157, which activates the mitochondrial calcium uniporter, increased both. BzATP induced rapid calcium influx in control AML cells but failed to elicit any rise in P2RX7-null cells, confirming the calcium signal is P2RX7 dependent. Overexpression of P2RX7 enhanced mitochondrial calcium accumulation and ROS, effects abolished by the uptake inhibitors. Critically, the mitochondria-targeted ROS scavenger mitoTEMPO sensitized P2RX7-overexpressing cells to chemotherapy, while the mitochondria-targeted pro-oxidant mitoPQ restored antioxidant activity and chemoresistance in P2RX7-deficient cells. This demonstrates that stromal cell-induced P2RX7 upregulation drives mitochondrial calcium overload and oxidative stress, which in turn activates adaptive antioxidant defences.

Downstream of mitochondrial stress, the study identifies the transcription factor Nrf2 as the essential effector. Under basal conditions, Nrf2 is bound by Kelch-like ECH-related protein 1, or Keap1, which promotes its continuous ubiquitin-proteasomal degradation and thereby maintains redox homeostasis. Upon oxidative stress, Nrf2 escapes Keap1-mediated degradation, accumulates and translocates to the nucleus, where it binds antioxidant response elements in the promoters of cytoprotective genes including CAT, NQO1 and HMOX1. In co-cultured AML cells, Nrf2 protein levels rose significantly while its messenger RNA remained unchanged, indicating post-transcriptional regulation. Genetic ablation of Nrf2 abolished the ability of P2RX7 overexpression to enhance antioxidant capacity and chemoresistance, establishing Nrf2 as the necessary downstream effector. ARE-driven luciferase reporter activity was impaired by P2RX7 knockout and enhanced by overexpression, with the latter effect suppressed by mitoTEMPO, confirming that mitochondrial oxidative stress is required for P2RX7-mediated Nrf2 activation.

How does P2RX7-driven mitochondrial stress stabilize Nrf2? The study identifies PGAM5, a protein anchored to the outer mitochondrial membrane, as the critical retrograde signalling hub. PGAM5 loss did not affect basal Nrf2 levels in monocultured cells but markedly attenuated the Nrf2 increase observed under stromal co-culture, and P2RX7 overexpression failed to induce Nrf2 accumulation in PGAM5-deficient cells. Neither mitoTEMPO nor mitoPQ altered Nrf2 levels in PGAM5-knockout cells, suggesting PGAM5 is essential for transducing mitochondrial ROS signals to Nrf2. PGAM5 deletion also abolished the ability of P2RX7 to enhance antioxidant capacity and chemoresistance. Co-immunoprecipitation experiments revealed that stromal co-culture promoted the interaction between PGAM5 and Keap1, whereas P2RX7 knockout impaired this interaction, and mitoPQ restored PGAM5-Keap1 binding in the absence of P2RX7. In PGAM5-deficient cells, P2RX7 overexpression was unable to disrupt the Keap1-Nrf2 complex. The relay model that emerges is one in which P2RX7-induced mitochondrial stress causes PGAM5 to engage Keap1, coinciding with reduced Keap1-Nrf2 binding, decreased Nrf2 ubiquitination, slower Nrf2 degradation, and activation of the Nrf2-ARE antioxidant programme.

Finally, the therapeutic implications were tested in vivo. In systemic AML mouse models established with HL-60 or U937 cells in immunodeficient NCG mice, and repeated in an MLL-AF9-driven murine AML model in C57BL/6 mice with normal immune systems, mice received vehicle, cytarabine, AZ10606120, or the combination for five consecutive days. Monotherapy with either agent had minimal impact on leukaemic burden, but combination therapy significantly reduced spleen and liver infiltration, decreased AML cell burden in the bone marrow, relieved hepatosplenomegaly, and significantly prolonged survival. Ex vivo analysis of residual bone marrow AML cells showed that AZ10606120 monotherapy reduced total antioxidant capacity and increased 8-OHdG accumulation, effects further exacerbated by combination treatment. The enhanced efficacy of cytarabine in vivo is therefore at least partially attributable to the ability of P2RX7 blockade to compromise antioxidant defences, rendering leukaemic cells more vulnerable to oxidative stress and chemotherapeutic damage. The researchers caution that clinical translation of P2RX7 inhibitors requires careful consideration of potential off-target effects given the receptor’s pleiotropic roles in immunity and normal tissue homeostasis, and note that highly selective antagonists and advanced delivery strategies such as liposomal or bone marrow-targeting systems could mitigate systemic exposure. They also emphasize that stromal cells interact with AML cells through multiple bidirectional mechanisms, including direct cell-cell contact, paracrine signalling and extracellular vesicles, raising the possibility of a feed-forward loop that reinforces the protective leukaemic niche. Future studies with larger, genotype-stratified primary AML cohorts and patient-derived xenograft models will be needed to determine whether this axis is preferentially active in specific molecular subtypes and whether it functionally intersects with other resistance pathways.

Subject of Research: Acute myeloid leukaemia

Article Title: Bone marrow stromal cells promote chemoresistance in acute myeloid leukaemia through P2RX7-mediated antioxidant defence

Article References: You, R., Wang, X., Zheng, X., Fang, W., Jiang, C., Liu, J., Xu, X., Tan, M., Cai, D., Hou, D., Zheng, J., Lin, X., & Huang, H. (2026). Bone marrow stromal cells promote chemoresistance in acute myeloid leukaemia through P2RX7-mediated antioxidant defence. Experimental & Molecular Medicine, 58(9), 3025-3041. https://doi.org/10.1038/s12276-026-01839-4

Image Credits: AI Generated

DOI: 10.1038/s12276-026-01839-4

Keywords: Bone, marrow, stromal, cells, promote, chemoresistance, acute, myeloid, leukaemia, P2RX7-mediated, antioxidant, defence

Chitosan has long attracted attention in biomedical research because of its unusual combination of properties. It is biocompatible, meaning the body tolerates it well, and it is biodegradable, breaking down into harmless byproducts over time. Its positively charged surface allows it to interact readily with cell membranes, and its chemical structure can be modified with relative ease. These characteristics make it an ideal scaffold for building nanoparticles that can carry therapeutic payloads, and the new review argues that this versatility is now being exploited in ways that directly address some of the most stubborn problems in gynecological oncology.

One of the central challenges in treating ovarian and cervical cancers is the toxicity of conventional chemotherapy. Standard drugs such as paclitaxel and cisplatin circulate throughout the body, damaging healthy tissue alongside tumors and producing side effects that often force treatment interruptions. Chitosan-based nanoplatforms offer a way around this problem by encapsulating the drugs and releasing them only when specific conditions are met. The review describes redox-responsive carriers, for example, that remain stable in the bloodstream but fall apart inside tumor cells, where the chemical environment differs sharply from that of healthy tissue. This triggered release concentrates the toxic payload where it is needed and spares the rest of the body.

Getting the drug into the cancer cell is only half the battle, however. The review highlights formulations that improve cellular uptake through targeted modifications, most notably the conjugation of folic acid to the nanoparticle surface. Many ovarian cancer cells overexpress folate receptors on their surfaces, effectively displaying a molecular handle that folate-decorated nanoparticles can grab. In studies involving ovarian cancer cell lines such as A2780 and SKOV-3, as well as the cervical cancer line HeLa, these targeted systems demonstrated enhanced cytotoxicity, greater pro-apoptotic activity, and reduced metastatic behavior compared with untargeted counterparts. Lipid-chitosan hybrid nanoparticles, which combine the membrane-fusing properties of lipids with the structural stability of chitosan, have also shown strong performance in these models.

Perhaps the most forward-looking section of the review concerns combination therapies that go beyond chemotherapy. Multifunctional platforms merging photothermal and photodynamic strategies with immunotherapy have produced improved antitumor effects in laboratory settings. In photothermal therapy, nanoparticles accumulate in the tumor and convert near-infrared light into localized heat, essentially cooking the cancer cells from within. Photodynamic therapy relies on light-activated compounds that generate reactive oxygen species, highly reactive molecules that destroy cellular structures and can also stimulate the immune system. When these approaches are combined with agents that activate immune responses, the dying tumor cells release antigens that can train immune cells to hunt down remaining cancer throughout the body, an effect researchers describe as turning the tumor itself into a vaccine.

The review also addresses chemoresistance, one of the most frustrating obstacles in ovarian cancer treatment. Patients frequently respond well to initial chemotherapy only to relapse with tumors that no longer respond to the same drugs. Chitosan nanocarriers can modulate this resistance by altering how drugs enter and accumulate within cancer cells, and by co-delivering agents that interfere with the molecular pumps and survival pathways that tumors use to shrug off treatment. By packaging multiple drugs together and controlling their release kinetics, these systems can attack resistance mechanisms from several directions at once.

Diagnosis and monitoring represent another dimension of the chitosan story. The review describes biosensing platforms built on chitosan scaffolds that can detect cancer biomarkers with high precision, enabling earlier diagnosis and continuous tracking of disease. Because chitosan films and nanoparticles provide a favorable environment for immobilizing recognition molecules such as antibodies and nucleic acid probes, they serve as sensitive transducer surfaces in electrochemical and optical biosensors. The authors suggest that such tools could eventually allow clinicians to catch recurrences before they become clinically apparent, when intervention is most likely to succeed.

Local and sustained drug delivery is a further area of active exploration. Advanced fabrication methods, including three-dimensional printed scaffolds, allow therapeutic materials to be implanted directly at the tumor site, where they release their payload over extended periods. This approach is particularly relevant to ovarian cancer, which tends to remain confined to the peritoneal cavity for much of its progression. Localized delivery reduces systemic exposure, minimizes side effects, and maintains high drug concentrations precisely where tumor cells reside, a combination that systemic intravenous chemotherapy struggles to achieve.

The translational path from laboratory bench to clinic remains demanding, and the authors are careful to frame their conclusions as promising rather than definitive. Most of the evidence reviewed comes from cell culture studies, and the journey through animal models, safety testing, and clinical trials has claimed many promising nanomedicines over the years. Questions about large-scale manufacturing consistency, long-term biocompatibility, and the behavior of nanoparticles in the complex environment of the human body will need answers before chitosan platforms reach routine clinical use. Nevertheless, the convergence of targeted chemistry, stimuli-responsive design, and combination therapy in a single biocompatible material gives the field an unusually coherent platform to build on.

What makes this review notable is its synthesis of an entire toolbox within one material system. A single chitosan nanoparticle can, in principle, be engineered to home in on tumor cells, release its cargo in response to the tumor’s internal chemistry, generate destructive heat or reactive oxygen species when illuminated, recruit the immune system to the fight, and report on its own progress through biosensing. For patients with ovarian and cervical cancers, diseases that together affect hundreds of thousands of women worldwide each year, such multifunctional platforms could eventually mean treatments that are simultaneously more effective and far gentler than today’s standards. The research community will be watching closely as these systems move from petri dish toward patient.

Subject of Research: Chitosan-based stimuli-responsive nanoplatforms for therapy and diagnosis of gynecological cancers

Article Title: Stimuli-responsive and multifunctional chitosan-based nanoplatforms in gynecological cancers therapy: mechanistic insights, immuno-phototherapeutic strategies, chemoresistance modulation, and translational perspectives

Article References: Sun, J., Yu, H., & Li, T. (2026). Stimuli-responsive and multifunctional chitosan-based nanoplatforms in gynecological cancers therapy: mechanistic insights, immuno-phototherapeutic strategies, chemoresistance modulation, and translational perspectives. Journal of Ovarian Research. https://doi.org/10.1186/s13048-026-02274-9

Image Credits: AI Generated

DOI: 10.1186/s13048-026-02274-9

Keywords: chitosan, nanoparticles, ovarian cancer, cervical cancer, drug delivery, photothermal therapy, photodynamic therapy, immunotherapy, chemoresistance, biosensors, targeted therapy, nanomedicine

The investigation began with a large-scale mapping exercise. The researchers combined single-cell proteomics data acquired through mass cytometry, a technique known as CyTOF that measures dozens of proteins on individual cells, with public transcriptomic datasets from the Gene Expression Omnibus and The Cancer Genome Atlas. This integrative analysis revealed that CD7 is not confined to a single obscure leukemia subtype. Instead, it appears across most AML subgroups, albeit at strikingly heterogeneous levels, and is consistently enriched on early-stage myeloid cells. That pattern is significant because immature cells are thought to harbor much of leukemia’s regenerative capacity, suggesting that CD7 expression marks a population with stem-like behavior and clinical menace.

To move beyond correlation, the team built cell lines with distinct CD7 expression levels and performed functional perturbation experiments, using short hairpin RNA to silence the protein where it was abundant and to introduce it where it was absent. The results were unambiguous. CD7 promoted leukemic cell fitness on several fronts simultaneously: it accelerated proliferation, pushed cells through the cell cycle more efficiently, and suppressed differentiation, the process by which immature blood cells would normally mature and lose their malignant potential. In other words, CD7 helps leukemia cells stay young, divide quickly, and refuse to grow up, a combination that oncologists recognize as a recipe for aggressive disease.

The most consequential finding, however, concerned chemotherapy. When CD7-expressing cells were exposed to cytarabine, a nucleoside analog that terminates DNA synthesis, and daunorubicin, an anthracycline that damages DNA and poisons topoisomerase II, they survived at doses that killed their CD7-negative counterparts. This resistance was not a side effect of faster growth or slower drug uptake alone. Instead, the researchers traced it to a signaling cascade centered on nuclear factor kappa B, the transcription factor better known as NF-κB, which sits at the crossroads of inflammation, immunity, and cell survival.

Using western blotting and immunofluorescence, the team showed that CD7-positive AML cells displayed enhanced activation of the NF-κB pathway, visible as the characteristic nuclear translocation of NF-κB subunits and the degradation of its inhibitor, IκBα. Once active, NF-κB reprogrammed gene expression in two directions that both favor drug survival. First, it drove transcriptional upregulation of P-glycoprotein 1, the famous multidrug efflux pump that expels chemotherapeutic agents from the cell before they can inflict lethal damage. Second, it sustained the expression of XIAP, the X-linked inhibitor of apoptosis protein, which blocks the caspase enzymes that execute programmed cell death. Together, these two arms of the NF-κB program allow CD7-positive leukemia cells to pump out the poison and refuse to die.

RNA sequencing reinforced the mechanistic picture. Gene set enrichment analysis and pathway mapping showed that the transcriptional landscape of CD7-positive cells was dominated by NF-κB target genes and inflammatory signaling modules, consistent with the protein-level observations. The study also considered other drug transport machinery, including the nucleoside transporter hENT1 and the efflux protein MRP4, which are relevant to cytarabine handling, but the dominant, CD7-dependent axis ran through P-glycoprotein 1 and XIAP under NF-κB control. This level of mechanistic detail matters because it converts CD7 from a statistical risk factor into a defined, targetable circuit.

Perhaps the most biologically intriguing part of the story involves the tumor microenvironment. The bone marrow of an AML patient is an inflammatory place, bathed in cytokines released by both malignant and stromal cells. The researchers found that inflammatory cytokines, specifically interleukin-1 beta and tumor necrosis factor alpha, selectively amplified NF-κB activation in a CD7-dependent manner. In cells lacking CD7, the same cytokines produced a far weaker response. This suggests that CD7 acts as an antenna that lets leukemia cells exploit the cytokine-rich soil of the marrow, converting the body’s own inflammatory signals into a survival program that includes drug efflux and apoptosis evasion. Chemotherapy itself can worsen this environment, raising the possibility of a vicious cycle in which treatment-induced inflammation further hardens the remaining leukemia cells against the next round of drugs.

The clinical implications are immediate and concrete. CD7 is already a familiar target in hematology because of its prominence on T-cell acute lymphoblastic leukemia, and CD7-directed immunotherapies, including antibody-drug conjugates and CAR-T cell constructs, are in active clinical development for T-cell malignancies. The new findings provide a mechanistic rationale for extending that arsenal to CD7-positive AML, particularly in patients whose disease has proven refractory to standard induction chemotherapy. Beyond direct targeting, the study highlights the downstream nodes as vulnerabilities in their own right: inhibitors of NF-κB signaling, P-glycoprotein function, or XIAP activity could, in principle, resensitize CD7-positive blasts to cytarabine and daunorubicin, restoring the effectiveness of drugs that have anchored AML therapy for half a century.

There are, of course, caveats that temper the excitement. NF-κB is a double-edged sword in human physiology, essential for immune defense, and systemic blockade carries well-known risks, so any therapeutic strategy will need to navigate toxicity carefully. The study relied partly on cell line models, and although the authors anchored their analysis in patient-derived single-cell data and samples collected with written informed consent under ethics approval from the Institute of Hematology and Blood Diseases Hospital, prospective validation in patient cohorts will be essential before CD7 becomes a routine stratification biomarker. Heterogeneous expression across subgroups also means that any CD7-directed approach will need companion diagnostics to identify the patients most likely to benefit.

Even with those qualifications, the study represents a satisfying resolution to a long-standing puzzle. A marker that clinicians have measured and worried about for years now has a coherent biological job description: it keeps leukemic cells immature and proliferative, arms them with drug pumps and anti-death machinery through NF-κB, and tunes them to the inflammatory chorus of the bone marrow. The work was supported by China’s National Key Research and Development Program and the National Natural Science Foundation of China, and it exemplifies how single-cell technology combined with classical molecular biology can turn a correlation into a mechanism. For patients with CD7-positive AML, a group that has long carried a worse prognosis, the message is one of cautious optimism: the enemy’s armor has been mapped, and each plate of that armor is now a potential point of attack.

Subject of Research: Mechanism by which CD7 promotes chemoresistance in acute myeloid leukemia through cytokine-dependent NF-κB signaling

Article Title: CD7 drives chemoresistance in acute myeloid leukemia via cytokine-dependent NF-κB signaling

Article References: Ren, C.-S., Shao, N., Yuan, Y., Cheng, T., Yi, H., Xu, H., Li, S.-M., Wang, D.-B., & Zhang, X.-E. (2026). CD7 drives chemoresistance in acute myeloid leukemia via cytokine-dependent NF-κB signaling. Journal of Experimental & Clinical Cancer Research. https://doi.org/10.1186/s13046-026-03835-y

Image Credits: AI Generated

DOI: 10.1186/s13046-026-03835-y

Keywords: acute myeloid leukemia, CD7, chemoresistance, NF-κB, cytarabine, daunorubicin, P-glycoprotein 1, XIAP, IL-1β, TNF-α, drug efflux, single-cell proteomics