Cancer Models Research Articles

Noninvasive Immunotyping and Immunotherapy Monitoring of Lung Cancers via Nuclear Imaging of LAG‐3 and PD‐L1

AbstractImmunotherapy has significantly improved cancer patient survival, while its efficacy remains limited due to the reliance on a single marker like PD‐L1 as well as its spatiotemporal heterogeneity. To address this issue, combining lymphocyte activation gene‐3 (LAG‐3) with PD‐L1 is proposed for identifying immunotypes and monitoring immunotherapy through nuclear imaging. In short, 99mTc‐HYNIC‐αLAG‐3 and 99mTc‐HYNIC‐αPD‐L1 probes are synthesized using anti‐human LAG‐3 and PD‐L1 antibodies, respectively. With high radiochemical purity and in vitro stability, these probes are confirmed to specifically bind to LAG‐3 or PD‐L1 in LAG3+ A549, LAG3− A549, and H1975 cells. SPECT/CT imaging of both probes showed specific in vivo tumor uptake in multiple lung cancer models, with significant linear correlation with ex vivo tumor uptake and immunohistochemical expression levels of LAG‐3/PD‐L1. Based on this, dual‐index imaging was performed to simultaneously quantify LAG‐3 and PD‐L1. SPECT/CT imaging of 99mTc‐HYNIC‐αLAG‐3 and 125I‐αPD‐L1 successfully distinguished four immunotypes. In addition, SPECT/CT imaging revealed LAG‐3 upregulation in LLC‐bearing LAG‐3 humanized mice resistant to immunotherapy. In conclusion, this study demonstrates the feasibility of nuclear imaging of LAG‐3 and PD‐L1 for both noninvasive immunotyping and immunotherapy monitoring, thus offering novel perspectives on forecasting immunotherapy response, uncovering resistance mechanism, and optimizing combination treatment regimens.

Resolution-dependent MRI-to-CT translation for orthotopic breast cancer models using deep learning

Resolution-dependent MRI-to-CT translation for orthotopic breast cancer models using deep learning

Loss of CDKN2A Enhances the Efficacy of Immunotherapy in EGFR Mutant Non-Small Cell Lung Cancer

Abstract Mutant epidermal growth factor receptor (EGFR) is a common driver of non-small cell lung cancer (NSCLC). While mutant EGFR has been reported to limit the efficacy of immunotherapy, a subset of EGFR mutant NSCLC patients benefit from treatment with immune checkpoint inhibitors. A better understanding of how co-occurring genomic alterations in oncogenic driver genes impact immunotherapy efficacy may provide a more complete understanding of cancer heterogeneity and identify biomarkers of response. Here, we investigated the effects of frequent EGFR co-mutations in EGFR mutant lung cancer models and identified loss-of-function mutation of CDKN2A as a potential sensitizer to anti-PD-1 treatment in vitro and in vivo. Mechanistically, CDKN2A loss impacted the composition of the tumor immune microenvironment (TIME) by promoting the expression of PD-L2 through reduced ubiquitination of c-Myc, and mutant EGFR cooperated to upregulate c-Myc and PD-L2 by activating the MAPK pathway. Blocking PD-L2 induced anti-tumor immune responses mediated by CD8+ T cells in EGFR/CDKN2A co-mutated lung cancer. Importantly, a small-molecule PD-L2 inhibitor, zinc undecylenate, remodeled the TIME of EGFR/CDKN2A co-mutant tumors and enhanced the anti-tumor efficacy of EGFR-tyrosine kinase inhibitors. Collectively, these results identify EGFR/CDKN2A co-mutation as a distinct subtype of NSCLC that shows superior sensitivity to immune checkpoint blockade and reveals a potential combined therapeutic strategy for treating this NSCLC subtype.

Smart Mesoporous Silica Nanoparticles Loading Curcumin Inhibit Liver Cancer.

Curcumin (CUR) as one of the natural edible pigments is approved by the World Health Organization due to its nontoxic and anticancer effect. However, the utility of CUR is restricted due to its low oral bioavailability. Nanoparticle drug delivery systems like mesoporous silica nanoparticles (MSNs) have been extensively used due to their high specific surface area, high loading rate, and ease of modification. This study developed lactobionic acid (LA)-modified carboxymethyl chitosan (CMCS)-coated MSNs to deliver CUR specifically targeting hepatocellular carcinoma. Among these nanoparticles, LA targets liver cancer cells. CMCS utilizes pH-responsive release of CUR. The LA-CMCS-MSN@CUR (MSN@CUR) were evaluated using several methods, including Fourier transform infrared spectroscopy, transmission electron microscopy, and zeta potential measurements. Liver cellular uptake of MSN@CUR depends on a specific LA receptor-mediated endocytosis mechanism. Additionally, MSN@CUR performed with a better antitumor effect than Cur in H22 orthotopic transplantation of liver cancer and H22 solid tumor mouse models. Treatment with MSN@CUR significantly reduced the protein of VEGF, p-PI3K, and AKT, increased the protein of caspases 3 and 8, ultimately inhibited tumor migration, and promoted apoptosis. This study provides a new path for delivery of natural active ingredients with excellent bioavailability in the antitumor field.

Cytotoxic Effects of Plant Secondary Metabolites and Naturally Occurring Bioactive Peptides on Breast Cancer Model Systems: Molecular Mechanisms

Breast cancer is the second leading cause of death among women, and the number of mortal cases in diagnosed patients is constantly increasing. The search for new plant compounds with antitumor effects is very important because of the side effects of conventional therapy and the development of drug resistance in cancer cells. The use of plant substances in medicine has been well known for centuries, but the exact mechanism of their action is far from being elucidated. The molecular mechanisms of cytotoxicity exerted by secondary metabolites and bioactive peptides of plant origin on breast cancer cell lines are the subject of this review.

Comparative analysis of canine and human HtrA2 to delineate its role in apoptosis and cancer.

Therapeutically, targeting the pro- and anti-apoptotic proteins has been one of the major approaches behind devising strategies to combat associated diseases. Human high-temperature requirement serine protease A2 (hHtrA2), which induces apoptosis through both caspase-dependent and independent pathways is implicated in several diseases including cancer, ischemic heart diseases, and neurodegeneration, thus making it a promising target molecule. In the recent past, the canine model has gained prominence in the understanding of human pathophysiology that was otherwise limited to the rodent system. Moreover, canine models in cancer research provide an opportunity to study spontaneous tumors as their size, lifespan, and environmental exposure are significantly closer to that of humans compared with laboratory rodents. Therefore, using HtrA2 as a model protein, comparative analysis has been done to revisit the hypothesis that canines might be excellent models for cancer research. We have performed evolutionary phylogenetic analyses that confirm a close relationship between canine and human HtrA2s. Molecular modeling demonstrates structural similarities including orientation of the catalytic triad residues, followed by in silico docking and molecular dynamics simulation studies that identify the potential interacting partners for canine HtrA2 (cHtrA2). In vitro biophysical and protease studies depict similarities in interaction with their respective substrates as well as transient transfection of cHtrA2 in mammalian cell culture shows induction of apoptosis. This work, therefore, promises to open a new avenue in cancer research through the study of spontaneous cancer model systems in canines.

A novel approach to engineering three-dimensional bladder tumor models for drug testing.

Bladder cancer (BCa) poses a significant health challenge, particularly affecting men with higher incidence and mortality rates. Addressing the need for improved predictive models in BCa treatment, this study introduces an innovative 3D in vitro patient-derived bladder cancer tumor model, utilizing decellularized pig bladders as scaffolds. Traditional 2D cell cultures, insufficient in replicating tumor microenvironments, have driven the development of sophisticated 3D models. The study successfully achieved pig bladder decellularization through multiple cycles of immersion in salt solutions, resulting in notable macroscopic and histological changes. This process confirmed the removal of cellular components while preserving the native extracellular matrix (ECM). Quantitative analysis demonstrated the efficacy of decellularization, with a remarkable reduction in DNA concentration, signifying the removal of over 95% of cellular material. In the development of the in vitro bladder cancer model, muscle invasive bladder cancer patients' cells were cultured within decellularized pig bladders, yielding a three-dimensional cancer model. Optimal results were attained using an air-liquid interface technique, with cells injected directly into the scaffold at three distinct time points. Histological evaluations showcased characteristics resembling in vivo tumors derived from bladder cancer patients' cells. To demonstrate the 3D cancer model's effectiveness as a drug screening platform, the study treated it with Cisplatin (Cis), Gemcitabine (Gem), and a combination of both drugs. Comprehensive cell viability assays and histological analyses illustrated changes in cell survival and proliferation. The model exhibited promising correlations with clinical outcomes, boasting an 83.3% reliability rate in predicting treatment responses. Comparison with traditional 2D cultures and spheroids underscored the 3D model's superiority in reliability, with an 83.3% predictive capacity compared to 50% for spheroids and 33.3% for 2D culture. Acknowledging limitations, such as the absence of immune and stromal components, the study suggests avenues for future improvements. In conclusion, this innovative 3D bladder cancer model, combining decellularization and patient-derived cells, marks a significant advancement in preclinical drug testing. Its potential for predicting treatment outcomes and capturing patient-specific responses opens new avenues for personalized medicine in bladder cancer therapeutics. Future refinements and validations with larger patient cohorts hold promise for revolutionizing BCa research and treatment strategies.

Induction of a distinct macrophage population and protection from lung injury and fibrosis by Notch2 blockade.

Macrophages are pleiotropic and diverse cells that populate all tissues of the body. Besides tissue-specific resident macrophages such as alveolar macrophages, Kupffer cells, and microglia, multiple organs harbor at least two subtypes of other resident macrophages at steady state. During certain circumstances, like tissue insult, additional subtypes of macrophages are recruited to the tissue from the monocyte pool. Previously, a recruited macrophage population marked by expression of Spp1, Cd9, Gpnmb, Fabp5, and Trem2, has been described in several models of organ injury and cancer, and has been linked to fibrosis in mice and humans. Here, we show that Notch2 blockade, given systemically or locally, leads to an increase in this putative pro-fibrotic macrophage in the lung and that this macrophage state can only be adopted by monocytically derived cells and not resident alveolar macrophages. Using a bleomycin and COVID-19 model of lung injury and fibrosis, we find that the expansion of these macrophages before lung injury does not promote fibrosis but rather appears to ameliorate it. This suggests that these damage-associated macrophages are not, by themselves, drivers of fibrosis in the lung.

Towards an emerging role for anticoagulants in cancer therapy: a systematic review and meta-analysis

BackgroundAnticoagulants, renowned for their role in preventing blood clot formation, have captivated researchers’ attention for the exploitation of their potential to inhibit cancer in pre-clinical models.ObjectivesTo undertake a systematic review and meta-analysis of the effects of anticoagulants in murine cancer research models. Further, to present a reference tool for anticoagulant therapeutic modalities relating to future animal pre-clinical models of cancer and their translation into the clinic.MethodsFour databases were utilized including Medline (Ovid), Embase (Ovid), Web of science, and Scopus databases. We included studies relating to any cancer conducted in murine models that assessed the effect of traditional anticoagulants (heparin and its derivatives and warfarin) and newer oral anticoagulants on cancer.ResultsA total of 6,158 articles were identified in an initial multi-database search. A total of 157 records were finally included for data extraction. Studies on heparin species and warfarin demonstrated statistically significant results in favour of tumour growth and metastasis inhibition.ConclusionOur findings constitute a valuable reference guide for the application of anticoagulants in cancer research and explore the promising utilization of non-anticoagulants heparin in preclinical cancer research.Systematic Review RegistrationPROSPERO [CRD42024555603].

Synergistic effect of the sphingosine kinase inhibitor safingol in combination with 2'-nitroflavone in breast cancer.

Sphingosine kinase-1 (SPHK1), the enzyme that catalyzes the synthesis of the pro-oncogenic molecule sphingosine-1-phosphate, is commonly upregulated in breast cancer cells and has been linked with poor prognosis and progression by promoting cell transformation, proliferation, angiogenesis, and metastasis. Therefore, SPHK1-targeting drugs have been proposed for breast cancer treatment, with better antitumor results when they are combined with chemotherapy. Previously, we demonstrated that the synthetic flavonoid 2'-nitroflavone (2'NF) exerted a potent and selective antiproliferative effect in murine HER2-positive LM3 mammary tumor cells. As we found that these cells overexpress SPHK1, we decided to explore the antitumor action of the combination of SPHK inhibitors (safingol or SKI-II) with 2'NF. In vitro assays showed that the combination induced a synergistic antiproliferative effect in LM3 cells. Similar results were obtained when human HER2-positive MDA-MB-453 breast cancer cells were treated with the combination of 2'NF/safingol. We also found that safingol potentiated the 2'NF apoptotic effect in both cell lines. The synergistic antitumor effect was confirmed in vivo in an LM3 syngeneic breast cancer model. Moreover, western blot analysis of tumor lysates revealed that combined treatment increased PARP cleavage and Bax protein levels and decreased anti-apoptotic Bcl-xL and Bcl-2 protein levels. Additionally, mice treated with both compounds showed no histopathological effects on different organ tissues. In summary, these findings suggest that the combination safingol/2'NF can be proposed as a potential therapeutic strategy for HER2-positive breast cancer treatment. KEY MESSAGES: The combination safingol/2'-nitroflavone exerts a synergic antitumor action in vitro. Safingol potentiates 2'-nitroflavone apoptotic effect in breast cancer cells. Safingol enhances the 2'-nitroflavone antitumor activity in vivo in breast cancer.

Enhancing transcription–replication conflict targets ecDNA-positive cancers

Extrachromosomal DNA (ecDNA) presents a major challenge for cancer patients. ecDNA renders tumours treatment resistant by facilitating massive oncogene transcription and rapid genome evolution, contributing to poor patient survival1–7. At present, there are no ecDNA-specific treatments. Here we show that enhancing transcription–replication conflict enables targeted elimination of ecDNA-containing cancers. Stepwise analyses of ecDNA transcription reveal pervasive RNA transcription and associated single-stranded DNA, leading to excessive transcription–replication conflicts and replication stress compared with chromosomal loci. Nucleotide incorporation on ecDNA is markedly slower, and replication stress is significantly higher in ecDNA-containing tumours regardless of cancer type or oncogene cargo. pRPA2-S33, a mediator of DNA damage repair that binds single-stranded DNA, shows elevated localization on ecDNA in a transcription-dependent manner, along with increased DNA double strand breaks, and activation of the S-phase checkpoint kinase, CHK1. Genetic or pharmacological CHK1 inhibition causes extensive and preferential tumour cell death in ecDNA-containing tumours. We advance a highly selective, potent and bioavailable oral CHK1 inhibitor, BBI-2779, that preferentially kills ecDNA-containing tumour cells. In a gastric cancer model containing FGFR2 amplified on ecDNA, BBI-2779 suppresses tumour growth and prevents ecDNA-mediated acquired resistance to the pan-FGFR inhibitor infigratinib, resulting in potent and sustained tumour regression in mice. Transcription–replication conflict emerges as a target for ecDNA-directed therapy, exploiting a synthetic lethality of excess to treat cancer.

Black raspberry modulates cecal and oral microbiome at the early stage of a dibenzo[def,p]chrysene-induced murine oral cancer model.

While tobacco smoking is a risk factor in the development of oral squamous cell carcinoma (OSCC), only a fraction of smokers develop the disease. Compelling evidence shows that microbial community composition is associated with carcinogenesis, suggesting that the microbiome may play a role in cancer development of smokers. We previously showed that black raspberry (BRB) protects against OSCC induced by the tobacco constituent dibenzo[def,p]chrysene (DBP) altering genetic and epigenetic markers in a manner consistent with its cancer preventive activity. In the present study, we conducted a mouse experiment to investigate the effects of BRB and DBP individually and in combination on the oral and gut microbiota. DBP-induced DNA damage in the mouse oral cavity which is an essential step for the development of OSCC in mice. 16S rRNA gene sequencing revealed that BRB significantly increased microbial diversity and shifted microbiome composition in the gut and oral cavity, whereas DBP had no significant effect. In both gut and oral microbiota, Akkermansia muciniphila was significantly reduced after BRB treatment; however, this was not consistent with pure culture in vitro assays suggesting that the impact of BRB on A. muciniphila may be mediated through indirect mechanisms including the host or other microbes. Indeed BRB, but not DBP, was found to modulate the growth kinetics of human gut microbes in vitro including lactic acid bacteria and Bacteroides spp. The results of the current study further emphasize the interplay of microbiome and environmental factors in the development and prevention of OSCC.

Intratumoral Injectable Redox-Responsive Immune Niche Improves the Abscopal Effect in Radiotherapy.

Radiotherapy (XRT) is often utilized to improve the immune checkpoint blockade response in cancer management. Such combination treatment can enhance the abscopal effect, facilitating a prolonged and durable systemic response. However, despite intense research efforts, only a minority of patients respond to this approach, and novel strategies to increase the abscopal effect are urgently needed. Here, the development of an intratumoral (i.t.) injectable nanofiber (NF)-based tumor immune niche (TIN) that converts XRT-treated tumors into an in situ cancer vaccine, eliciting robust systemic antitumor immunity, is reported. This NF-based immune niche incorporates redox-degradable anti-CTLA-4 (α-CTLA-4) nanogels (NGs) and interleukin-2 (IL-2) NGs for controlled release in hypoxic irradiated tumors, reversing the immunosuppressive tumor microenvironment into a pro-inflammatory microenvironment, and expanding the tumor-infiltrating CD8+ T cell population. Additionally, it is functionalized with polyinosinic-polycytidylic acid (poly(I:C)) to promote antigen-presenting cell maturation and prime neoantigen-specific CD8+ T cells. In vitro studies demonstrate TIN's ability to prime antigen-specific CD8+ T cells and increase antigen-specific cell-killing efficiency under in vitro immunosuppressive conditions. In vivo studies confirm TIN's ability to elicit robust systemic anticancer activity in mouse melanoma and colorectal cancer models without inducing severe immune-related adverse events.

Shrinking Cancer Research Barriers: Crafting Accessible Tumor‐on‐Chip Device for Gene Silencing Assays

Tumor‐on‐chip (ToC) is crucial to bridge the gap between traditional cell culture experiments and in vivo models, allowing to recreate an in vivo‐like microenvironment in cancer research. ToC use microfluidics to provide fine‐tune control over environmental factors, high‐throughput screening, and reduce requirements of samples and reagents. However, creating these microfluidic devices requires skilled researchers and dedicated manufacturing equipment, making widespread adoption cumbersome and difficult. To address some bottlenecks and improve accessibility to ToC technology, innovative materials and fabrication processes are required. Polystyrene (PS) is a promising material for microfluidics due to its biocompatibility, affordability, and optical transparency. Herein, a fabrication process based on direct laser writing on thermosensitive PS, allowing the swift and economical crafting of devices with easy pattern alterations, is presented. For the first time, a device for cell culture fabricated only by PS is presented, allowing customizing and optimization for efficient cell culture approaches. These biochips support 2D and 3D cultures with comparable viability and proliferation kinetics to traditional 96‐well plates. The data show that gene and protein silencing efficiencies remain consistent across both chip and plate‐based cultures, either 2D culture or 3D spheroid format. Although simple, this approach might facilitate the use of customized chip‐based cancer models.

Inhibition of GPX4 enhances CDK4/6 inhibitor and endocrine therapy activity in breast cancer.

CDK4/6 inhibition in combination with endocrine therapy is the standard of care for estrogen receptor (ER+) breast cancer, and although cytostasis is frequently observed, new treatment strategies that enhance efficacy are required. Here, we perform two independent genome-wide CRISPR screens to identify genetic determinants of CDK4/6 and endocrine therapy sensitivity. Genes involved in oxidative stress and ferroptosis modulate sensitivity, with GPX4 as the top sensitiser in both screens. Depletion or inhibition of GPX4 increases sensitivity to palbociclib and giredestrant, and their combination, in ER+ breast cancer models, with GPX4 null xenografts being highly sensitive to palbociclib. GPX4 perturbation additionally sensitises triple negative breast cancer (TNBC) models to palbociclib. Palbociclib and giredestrant induced oxidative stress and disordered lipid metabolism, leading to a ferroptosis-sensitive state. Lipid peroxidation is promoted by a peroxisome AGPAT3-dependent pathway in ER+ breast cancer models, rather than the classical ACSL4 pathway. Our data demonstrate that CDK4/6 and ER inhibition creates vulnerability to ferroptosis induction, that could be exploited through combination with GPX4 inhibitors, to enhance sensitivity to the current therapies in breast cancer.

Stability Analysis of Four-Dimensional Fractional Cancer Model via Caputo and Caputo-Fabrizio Derivatives

Stability Analysis of Four-Dimensional Fractional Cancer Model via Caputo and Caputo-Fabrizio Derivatives

Capivasertib augments chemotherapy via Akt inhibition in preclinical small cell lung cancer models.

Small cell lung cancer (SCLC) is a highly aggressive type of lung cancer for which platinum-based chemotherapy is the standard of care. Despite an initial response to this therapy, patients eventually develop resistance to the chemotherapy. To investigate the potential of capivasertib, an approved drug for advanced breast cancer, to enhance the efficacy of cisplatin in preclinical SCLC models and explore the underlying mechanisms. SCLC cell lines were treated with capivasertib and cisplatin, alone or in combination, to assess cell viability, proliferation, colony formation, and apoptosis. Next, capivasertib's effects, alone and combined with cisplatin, were evaluated in an SCLC mouse model. Mechanistic studies focused on Akt and MYC signaling, with constitutively active Akt overexpression used to assess its role. Capivasertib is active against a panel of SCLC cell lines regardless of cellular origin and genetic profiling with IC50 at a clinically achievable range. Particularly, capivasertib inhibits proliferation and anchorage-independent colony formation and induces apoptosis in SCLC cells. It significantly augments cisplatin's inhibitory effects in all tested cell lines. Importantly, capivasertib at a non-toxic dose is effective in delaying SCLC growth in mice and its combination with cisplatin achieves nearly complete tumor growth inhibition. Mechanistic studies confirm that capivasertib inhibits Akt and MYC signaling, and furthermore, that overexpression of constitutively active Akt reversed anti-SCLC activity of capivasertib. Our work is the first to reveal that Akt inhibition can augment chemotherapy in SCLC, and capivasertib is a useful addition to the treatment armamentarium for SCLC.

A Multi-Enzyme Nanocascade to Target Disease-Relevant Metabolites.

Metabolic processes in living organisms depend on the synergistic actions of enzymes working in proximity and in concert, catalyzing reactions effectively while regulating the formation of metabolites. This enzyme synergy offers promising therapeutic application for diseases such as alcohol intoxication, cancer, and hyperinflammation. Despite their potential, the clinical translation of enzyme cascades is restricted by challenges including poor enzyme stability, short half-life, and a lack of delivery strategies that maintain enzyme proximity. In this study, multi-enzyme nanocascades synthesized are developed through in situ atom transfer radical polymerization using a zwitterionic monomer. This method markedly enhances enzyme stability and proximity, thereby prolonging their circulation half-life after systemic administration. It is demonstrated that the nanocascades of uricase and catalase effectively reduce uric acid levels without excessive hydrogen peroxide production, providing a potential antidote for hyperuricemia. Moreover, in a murine breast cancer model, the nanocascades of glucose oxidase and catalase inhibited tumor progression and enhanced the therapeutic efficacy of doxorubicin. The prolonged circulation and promoted reaction efficacy of these nanocascades underscore their substantial potential in enzyme replacement therapy and the treatment of various diseases.

Evaluation of a Radioiodinated G-Quadruplex Binder in Cervical Cancer Models.

We herein describe the radiosynthesis of a 125I-labeled acridine orange derivative ([125I]-C8), acting as a G-quadruplex binder, and its biological evaluation in cervical cancer models, aiming to enlighten its potential as a radioligand for Auger Electron Radiopharmaceutical Therapy (AE-RPT) of cancer. [125I]-C8 was synthesized with a moderate radiochemical yield (ca. 60 %) by a [125I]iodo-destannylation reaction. Its evaluation in cervical cancer HeLa cells demonstrated that the radiocompound has a significant cellular internalization with a notorious accumulation in the cell nucleus. In line with these results, [125I]-C8 strongly compromised the viability of HeLa cells in a dose-dependent manner, inducing non-repairable DNA lesions that are most probably due to the AEs emitted by 125I in close proximity to the DNA molecule. Biodistribution studies in a murine HeLa xenograft model showed that [125I]-C8 has fast blood clearance and high in vivo stability but poor tumor uptake, after systemic administration. The respective supramolecular conjugate with the AS1411 aptamer ([125I]-C8/AS1411) led to a slower blood clearance in the same animal tumor model, although without improving the tumor uptake. To take advantage of the radiotoxicity of [125I]-C8 against cervical cancer cells other strategies need to be studied, based namely on alternative nanodelivery carriers and/or intratumoral injection approaches.

Single-cell sequencing unveils mitophagy-related prognostic model for triple-negative breast cancer

BackgroundTriple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer lacking hormone receptors and HER2 expression, leading to limited treatment options and poor prognosis. Mitophagy, a selective autophagy process targeting damaged mitochondria, plays a complex role in cancer progression, yet its prognostic significance in TNBC is not well understood.MethodsThis study utilized single-cell RNA sequencing data from the TCGA and GEO databases to identify mitophagy-related genes (MRGs) associated with TNBC. A prognostic model was developed using univariate Cox analysis and LASSO regression. The model was validated across multiple independent cohorts, and correlations between MRG expression, immune infiltration, and drug sensitivity were explored.ResultsNine key MRGs were identified and used to stratify TNBC patients into high-risk and low-risk groups, with the high-risk group showing significantly worse survival outcomes. The model demonstrated strong predictive accuracy across various datasets. Additionally, the study revealed a correlation between higher MRG expression levels and increased immune cell infiltration, as well as potential responsiveness to specific chemotherapeutic agents.ConclusionThe mitophagy-related prognostic model offers a novel method for predicting outcomes in TNBC patients and highlights the role of mitophagy in influencing the tumor microenvironment, with potential applications in personalized treatment strategies.