Search Results (1,129)

Intercellular mitochondrial trafficking has emerged as an important mechanism influencing tumor progression, metabolic adaptability, and cancer cell plasticity. Beyond their classical bioenergetic functions, mitochondria act as central regulators of redox homeostasis, signaling pathways, and epigenetic remodeling. Increasing evidence suggests that mitochondria can be transferred between tumor, stromal, and immune cells through tunneling nanotubes (TNTs), extracellular vesicles (EVs), gap junctions, and cell fusion within the tumor microenvironment. This dynamic excshange enables metabolically compromised cancer cells to restore oxidative phosphorylation, optimize energy production, and survive under hypoxia and therapeutic stress. Mitochondrial transfer has been increasingly associated with enhanced cellular plasticity and adaptive phenotypic transitions, including the acquisition of stem-like features that contribute to tumor heterogeneity, metastasis, and treatment resistance. In addition to bioenergetic restoration, transferred mitochondrial DNA and metabolites participate in retrograde signaling, linking metabolic state to epigenetic regulation and transcriptional reprogramming. This metabolic epigenetic interplay supports tumor cell adaptation to environmental stress and therapeutic pressure. Although significant progress has been made, the precise mechanisms governing mitochondrial integration and their long-term impact on cellular phenotypes remain incompletely understood. A deeper understanding of these processes may reveal novel therapeutic strategies to disrupt tumor adaptability and progression. Specifically, targeting intercellular mitochondrial trafficking and its associated metabolic and epigenetic effects could help limit tumor plasticity, overcome treatment resistance, reduce disease recurrence, and improve overall clinical outcomes in cancer patients. Full article

Prostate cancer (PCa) remains lethal at advanced stages, partly due to stem-like subpopulations known as prostate cancer stem cells (PCSCs) that sustain tumor growth and therapeutic resistance. Imipridones are small-molecule anticancer agents, with next-generation derivatives ONC206 and ONC212 designed for enhanced potency and broader activity. This study compared their antitumor efficacy and mechanisms in advanced androgen-independent PCa (AIPC) models, namely DU145 and PC3 cells, using two- and three-dimensional systems encompassing bulk cancer cells and PCSCs. DU145 and PC3 AIPC cells were treated with ONC201 (parent compound), ONC206, or ONC212. Functional assays assessed proliferation, viability, migration, invasion, PCa spheroids formation, cell cycle distribution, and mitochondrial membrane potential and mass, while RNA sequencing defined transcriptional responses. ONC212 was the most potent derivative, inhibiting proliferation and migration and abolishing PCa spheroids at nanomolar doses, whereas ONC201 and ONC206 required higher concentrations. Transcriptomic analyses revealed shared repression of DNA replication and cell-cycle transition programs, with activation of integrated stress and unfolded protein responses (ISR/UPR) and FOXO signaling. ONC206 favored PERK–ATF4-mediated apoptosis with reduced DNA repair, while ONC212 more strongly impacted oxidative phosphorylation-related pathways and mitochondrial RNA processing. Imipridones induced a time-dependent cell-cycle redistribution with increased sub-G1 accumulation and modulated mitochondrial membrane potential and mass in a context-dependent manner. Collectively, these findings position ONC212 as a leading imipridone candidate in AIPC models, combining potent inhibition of tumor and stem-like cell functions with a coherent stress-response signature that supports further translational evaluation. Full article

Endometriosis is a chronic estrogen-dependent inflammatory disease affecting approximately 10% of women of reproductive age and characterized by ectopic endometrial-like tissue growth. Although traditionally considered a benign gynecological condition, increasing evidence indicates that endometriosis shares several molecular and cellular features with malignant processes, including enhanced proliferation, resistance to apoptosis, invasive behavior, and the ability to remodel the surrounding microenvironment. Recent studies suggest that dysregulated estrogen signaling, particularly the imbalance between estrogen receptor subtypes, plays a central role in driving these processes and may contribute to the persistence and progression of ectopic lesions. In parallel, also the involvement of stem or progenitor cells has been highly investigated because they may support lesion establishment, cellular plasticity, and long-term disease maintenance. These mechanisms overlap with pathways commonly involved in tumor initiation and progression. Recognizing endometriosis as a stem cell-driven and estrogen-dependent condition, the perspective, in both clinical management and therapeutic strategies fields, can change. Indeed, it is essential to emphasize that endometriosis is a benign condition and that the risk of developing an associated tumor is very low, approximately 1.5–2%. This review aims to discuss current evidence on the molecular aspects, focusing on estrogen signaling, stem cell-related mechanisms, and inflammatory and microenvironmental pathways that contribute to disease development. By highlighting these mechanisms, an integrated perspective on the pathophysiology of endometriosis is provided, also to outline potential implications for biomarker discovery and targeted therapeutic strategies. Full article

Hypoxia is a hallmark feature of solid tumors and is increasingly recognized as an important factor in tumor progression, aggressiveness, and therapeutic resistance. In the tumor microenvironment, hypoxia is associated with genetic instability, abnormal angiogenesis, metabolic reprogramming, and crosstalk with oncogenic signaling pathways, thereby potentially enhancing tumor invasiveness and metastatic potential. Furthermore, hypoxia may impair the sensitivity of tumor cells to conventional therapies and contribute to treatment resistance. This article reviews current evidence on the role of hypoxia in thyroid cancer, focusing on its biological effects, clinical implications, and therapeutic relevance. Available studies suggest that hypoxia may affect thyroid cancer progression and treatment tolerance by modulating hypoxia-inducible factor (HIF) signaling, epithelial–mesenchymal transition (EMT), angiogenesis, metabolic adaptation, cancer stem-like properties, extracellular matrix remodeling, and stress-adaptive responses. However, the strength of evidence varies across these pathways, and many hypoxia-targeted strategies remain under preclinical investigation. Approaches such as HIF inhibition, redifferentiation therapy, and vascular modulation may offer potential therapeutic directions for advanced and refractory thyroid cancer. Given the marked heterogeneity of thyroid cancer, further thyroid cancer-specific studies are needed to clarify the prognostic and therapeutic significance of hypoxia. Full article

The tumor microenvironment (TME) is a highly adaptive and heterogeneous niche in which cancer stem cells (CSCs) promote immune evasion, metastatic dissemination, and therapy resistance. Among the mechanisms that support this phenotype, mitochondrial hijacking has emerged as a central strategy through which CSCs reprogram immune and stromal cells to favor tumor progression. This review synthesizes current evidence on how CSCs exploit mitochondrial transfer, particularly via tunneling nanotubes (TNTs) and extracellular vesicles (EVs), to impair antitumor immunity and remodel the metastatic niche. CSCs display marked metabolic plasticity, shifting between glycolysis and oxidative phosphorylation (OXPHOS) in response to environmental stress. They exploit this adaptability by transferring mitochondria and mitochondrial components to recipient cells, including tumor-associated macrophages (TAMs) and cytotoxic T cells, thereby disrupting ATP production, increasing oxidative stress, and skewing immune polarization. This mitochondrial hijacking contributes to an immunosuppressive milieu, stabilizes HIF-1α, and enhances PD-L1 expression, ultimately weakening T-cell activity and reinforcing CSC survival. EVs add another layer of regulation by transporting bioactive cargo, including oncogenic microRNAs (miRNAs) and mitomiRs such as miR-21, miR-210, and miR-34a. These molecules modulate mitochondrial gene expression, reshape immune signaling, and reinforce CSC phenotypes through autocrine and paracrine loops. Single-cell and spatial transcriptomic approaches have further revealed metabolic heterogeneity within CSC–immune synapses, identifying “metabolic hotspots” associated with profound immune dysfunction. Therapeutic strategies targeting OXPHOS, EV biogenesis, and miRNA activity are therefore being explored. In parallel, mitochondria-associated proteins such as TSGA10 may also contribute to CSC-driven immunometabolism regulation and deserve further investigation. Targeting downstream heterogeneity is like cutting the branches of a weed. Targeting the upstream mechanisms of mitochondrial hijacking and miRNA crosstalk aims to destroy the root (CSC plasticity) that generates the heterogeneity and drives therapy resistance in the first place. This review highlights mitochondrial hijacking and miRNA-mediated reprogramming as central determinants of CSC-driven immune escape and proposes a framework for precision interventions targeting CSC–immune interactions in metastatic cancer. Full article

Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TILs) has achieved clinically and biologically relevant responses in patients with solid cancer. Clinical efficacy has been increasingly linked to a specific T-cell phenotype, particularly CD8⁺ TILs exhibiting a progenitor stem-cell-like profile (CD39⁻ CD69⁻). This review explores the critical role of the sphingosine-1-phosphate (S1P) axis in orchestrating these responses. We detail the biological antagonism between the activation marker CD69 and S1P receptor 1 (S1PR1), where mutual exclusivity dictates thymic selection, if T-cells are retained in tissues or allowed to recirculate and maintain long-term immune surveillance. The S1PR1:S1P axis is further recognized as a critical regulator of mitochondrial fitness, sustaining the high energetic demands of precursor T-cells. We examine the “double-edged sword” nature of S1P in the tumor microenvironment (TME), where it can drive pro-tumorigenic processes like angiogenesis and vascular mimicry (VM), be hijacked by cancer cells to create immune-excluded environments, or S1P can increase T-cell fitness. We summarize the current landscape of clinical trials (as of January 2026) that target S1P production or signaling to modulate anti-tumor responses or use S1P as a biologically relevant marker of treatment outcome. Full article

Cancer progression is accompanied by significant metabolic alterations. We developed a novel computational approach to identify cancer-related risk metabolic subpathways (CMSubpathway). By leveraging the topology of large-scale metabolic pathway gene networks, we initially identified metabolic subpathways and then refined them by taking into account pathway activity dysregulation, prognostic efficacy, and classification performance. We employed the CMSubpathway to extensively identify cancer-related metabolic subpathways across 21 cancer types. Ultimately, 12 risk metabolic subpathways were identified in six cancer types. Subsequently, the 12 overlapping genes of risk metabolic subpathways were identified as the core metabolic module genes. Utilizing the public CRISPR knockout screening datasets sourced from DepMap, we further supported our hypothesis that the essential roles of ADH5, ALDH1B1, and ALDH7A1 in breast cancer cell growth and development. The core metabolic module and its associated genes exhibited significant down-regulation at both the transcriptome and proteome levels based on data from tissues, blood, and single cells. The activity of this core metabolic module was associated with the immune infiltration levels of multiple immune cells, especially T cells. Notably, an abnormal core metabolic module was observed in CD8 T cell subtypes, with the stem-like CD8 T cell subtype showing high metabolic activity and exhaustion markers. Thus, we established a method for identifying risk metabolic subpathways in cancers, which helps to identify more precise biomarkers for cancer patients. Full article

Drug resistance represents one of the most critical challenges in modern medicine, undermining the efficacy of therapies across both bacterial infections and cancer. Although these conditions arise in fundamentally distinct biological systems, they are governed by shared evolutionary pressures that drive the emergence and selection of resistant populations. This narrative review provides an integrative, cross-disciplinary perspective on drug resistance, focusing on bacteria and cancer and emphasizing the shared evolutionary and molecular mechanisms underlying treatment failure in both domains. Key resistance strategies include efflux-mediated drug export, target modification, enzymatic drug inactivation, metabolic reprogramming, epigenetic and transcriptional plasticity, and protection conferred by specialized microenvironments. These processes are further reinforced by phenotypic heterogeneity, including bacterial persister cells and cancer stem-like cells, which contribute to recurrence and multidrug resistance. Collectively, these parallels define drug resistance as a convergent evolutionary phenomenon driven by adaptability under selective pressure. Recognizing these shared mechanisms reveals important translational opportunities for therapeutic intervention. Strategies such as combination therapy, drug repurposing, nanotechnology-enabled delivery systems, and host-directed approaches offer promising avenues to prevent, delay, or overcome resistance. By integrating insights from microbiology and oncology, this review proposes a unified framework for resistance biology and highlights the potential of cross-disciplinary strategies to improve treatment durability and clinical outcomes. Full article

Soft tissue sarcomas (STS) comprise a rare and highly heterogeneous group of mesenchymal-derived malignancies, accounting for less than 1% of all cancers and characterized by diverse histologic and molecular subtypes. Despite their low incidence, STS account for a disproportionate burden of cancer-related morbidity and mortality, largely driven by their risk of metastatic dissemination. Early detection of metastatic spread is a cornerstone of preoperative staging, treatment planning, and postoperative monitoring in patients with STS. Although conventional imaging modalities remain fundamental for surveillance of metastatic disease, they may fail to accurately detect metastatic sites and provide limited insight into tumor biology. Advances in precision medicine have positioned liquid biopsy as a minimally invasive approach for the analysis of tumor-derived material, facilitating characterization of tumor biology and identification of prognostic biomarkers. Circulating tumor cells (CTCs) represent intact and viable tumor cells that provide unique genomic and phenotypic traits that could not be assessed using acellular tumor-derived material. They have emerged as promising biomarkers for monitoring disease progression, assessing treatment response, and stratifying prognosis. Particularly, their clinical value as prognostic biomarkers has been established in epithelial-derived malignancies. Despite these advances, the role of CTCs in STS remains largely investigational, mainly due to STS heterogeneity and the lack of standardized protocols for detection across platforms. Therefore, this narrative review summarizes the biomolecular mechanisms underlying CTCs in STS, including the role of phenotypic plasticity in tumor intravasation, anoikis resistance and its interaction with the tumor microenvironment, and stem cell-like phenotypes in tumor initiation at distant sites. Furthermore, we discuss current methodologies for CTC detection, highlighting emerging approaches developed to address the limitations of conventional methods. Finally, we provide a critical overview of subtype-specific detection strategies, as well as their clinical implications in treatment response monitoring and prognostic assessment. Full article

Vasculogenic mimicry (VM) is the ability of cancer stem cells (CSCs) to express an endothelial-like phenotype and participate in tumor neovascularization via the formation of a blood-conducting, matrix-rich network. We previously reported that pancreatic ductal adenocarcinoma (PDAC) CSCs develop their VM phenotype via two interacting and coordinated factors that support the formation of the VM network: (i) the overexpression of genes for endothelial factors and vascular receptors and (ii) the very high secretion of numerous pro-angiogenic/growth factors. While microenvironmental acidosis (low pHe) is an important driver of tumor metastasis, especially in PDAC, and is a component of the CSC niche, its role in VM and the ion transporters involved remains unknown. As normal stem cell differentiation is regulated by Na⁺/H⁺ exchanger 1 (NHE1)-driven pH, we investigated the role of NHE1 and the intracellular signaling involved in the acidosis-induced VM using a platform of 3D organotypic cultures composed of Matrigel with increasing concentrations of Collagen I. VM was highest on 90% Matrigel:10% Collagen I, representative of an early tumor ECM, and it decreased with increasing concentrations of Collagen I, representative of advanced tumors. In all ECM compositions, VM capacity increased stepwise with pHe acidification, and both basal and acid-stimulated VM were dependent on NHE1 activity. Acidification also decreased resting pHi and increased NHE1 proton extrusion activity, NHE1/ß1 integrin co-expression, and intracellular Ca²⁺. The stimulation of VM by extracellular acidosis depended on the transport of extracellular Ca²⁺ into the cell and the consequent increase in intracellular Ca²⁺. Altogether, these data demonstrate that extracellular acidification triggers cellular mechanisms that upregulate VM to overcome the constraints imposed by ECM composition, thereby permitting VM in ECMs where this phenotype is not expressed and extending the VM phenotype towards the tumor center to further drive metastasis. Full article

Hematological malignancies, including multiple myeloma (MM), leukemia, and lymphoma, represent a major global health burden, accounting for approximately 6.6% of all cancer cases and contributing to significant mortality. The evolutionary conserved WNT/β-catenin signaling pathway is a critical regulator of normal hematopoietic stem cell homeostasis, and its dysregulation is a hallmark of various hematological malignancies. Aberrant activation through mutations, overexpression of ligands, or disruption of the destruction complex drives uncontrolled proliferation, impaired differentiation, and therapeutic resistance to therapy in acute and chronic leukemias, lymphomas, and multiple myeloma. Therapeutic interventions targeting this pathway, such as GSK-3 inhibitors, β-catenin antagonists, and small molecules like CWP291 and salinomycin, have demonstrated promising antitumor effects. Furthermore, combining WNT/β-catenin inhibition with targeted or epigenetic therapies, such as venetoclax and chidamide, can produce synergistic antitumor effects and overcome chemoresistance. Despite this potential, clinical translation is hampered by on-target toxicities in healthy tissues, pathway complexity, and a lack of predictive biomarkers. We conclude that the future of WNT-directed therapy lies in developing biomarker-selective agents, advanced drug delivery systems to improve specificity, and exploring novel combinations with immunotherapy to harness the anti-tumor immune response. Full article

Breast cancer stem-like cells (bCSCs) fundamentally represent a highly dynamic “immune-adaptive functional state” rather than a fixed cellular lineage, serving as the core engine driving tumor recurrence, metastasis, and therapeutic resistance. Despite rapid advances, the heterogeneity of bCSC states and their intricate interactions with the immune microenvironment lack systematic integration. This review centers on the dynamic evolution and niche adaptation of bCSCs. First, we systematically dissect the multilayered regulatory network maintaining stemness, encompassing core transcription factors, epigenetic–metabolic coupling, and the synergistic mechanisms of critical signaling pathways such as Wnt and Notch. Second, we propose a trinary “stemness–immune–spatial” feedback model, elucidating how bCSCs achieve active immune evasion by downregulating antigen presentation, secreting immunosuppressive factors, and embedding within perivascular “immune-cold niches.” Finally, leveraging a multi-omics integration perspective, we reconstruct precision intervention strategies, exploring the synergistic potential of targeting stemness pathways in conjunction with immunotherapies like PD-1/PD-L1 blockade and STING agonists. Furthermore, we highlight the pivotal role of integrating organoids, PDX models, and AI-assisted decision systems in overcoming heterogeneity and enabling personalized treatment. By establishing a closed-loop framework spanning mechanistic insight to spatially precise intervention, this review aims to provide novel theoretical foundations and translational pathways to surmount the bottleneck of therapeutic resistance in breast cancer. Full article

Triple-negative breast cancer (TNBC) remains one of the most challenging subtypes of breast cancer to treat, defined by its molecular heterogeneity, absence of hormone receptors, and poor clinical outcomes. While this difficulty with cancer cells persists even in the presence of chemotherapy and immune checkpoint inhibitors (ICIs), one critical factor linked to both chemoresistance and immune escape is autophagy. Autophagy is a cellular process with lysosomal recycling function. In TNBC, autophagy paradoxically shifts from tumor-suppressive to a tumor-promoting role. Autophagy was initially known to maintain genomic stability and alleviate oxidative damage. In TNBC, cancer cells use autophagy to detoxify platinum-induced DNA. damage, clear damaged mitochondria via mitophagy, recycle critical macromolecules, and sustain dormancy in cancer stem-like cells (CSCs). At the same time, the process of autophagic flux facilitates immune evasion, including PD-L1 expression stabilization, MHC-I degradation, and the establishment of an immunosuppressive tumor microenvironment (TME). The review encapsulates the progressive concepts of molecular regulation of autophagy, which involve key factors such as ULK1, VPS34, and non-coding RNAs (ncRNAs). These factors play a significant role in chemoresistance, taxanes, anthracyclines, and platinum compounds. The review also discusses various strategies for translation that aim to circumvent or suppress autophagy-mediated chemoresistance, including autophagy inhibitors, natural compounds, and nanoparticle-based formulations, with a focus on their synergistic potential with ICIs and chemotherapeutic agents. Targeting autophagy has shown considerable potential for effectively addressing chemoresistance in TNBC. Future studies should focus on addressing chemoresistance and immunoresistance through autophagy-based therapies. Full article

Background/Objectives: Clear cell renal cell carcinoma is the most common subtype of kidney cancer and exhibits marked biological heterogeneity, even among tumors of the same histological grade. Although tumor grade remains a key prognostic parameter, the molecular alterations associated with tumor differentiation are not fully understood. This study aimed to evaluate grade-dependent tissue-level expression patterns of proteins involved in cellular stress response, growth regulation, stemness, and apoptosis in clear cell renal cell carcinoma. Methods: Protein expression of heat shock protein 70, insulin-like growth factor 1, octamer-binding transcription factor 4, and apoptosis-inducing factor were analyzed in human clear cell renal cell carcinoma samples and normal renal cortex. Low-grade and high-grade tumors were compared using immunofluorescence staining combined with semi-quantitative and quantitative image analysis. The proportion of positive signals and the number of positive cells were assessed across tissue compartments. In addition, publicly available transcriptomic data from The Cancer Genome Atlas kidney renal clear cell carcinoma cohort were analyzed to explore associations between gene expression levels and overall survival. Results: Distinct grade-dependent expression patterns were observed for all investigated proteins. Heat shock protein 70, insulin-like growth factor 1, and octamer-binding transcription factor 4 showed a higher expression in normal renal tissue with a progressive reduction across tumor grades. In contrast, apoptosis-inducing factor exhibited increased expression in tumor tissue, particularly in low-grade tumors, with a relative decrease in high-grade carcinomas. Stromal compartments of tumor tissue showed minimal or no expression for most markers. Transcriptomic survival analysis did not reveal significant differences in overall survival between high- and low-expression groups for any of the investigated genes. Grade-stratified transcriptomic analysis of the TCGA KIRC cohort revealed consistent patterns for HSP70 family members and OCT4, with progressive grade-dependent mRNA reduction toward higher grades, while IGF1 showed an inverse mRNA trend and AIFM1 showed a uniform reduction across all tumor grades without a clear inter-grade pattern. Conclusions: The findings demonstrate that stress response, growth-related, stemness-associated, and apoptotic proteins display distinct grade-dependent tissue-level expression patterns in clear cell renal cell carcinoma, with the expression profiles of high-grade tumors being of particular translational interest given the aggressive clinical behavior and therapeutic resistance characteristic of this disease stage. These alterations appear to reflect tumor differentiation and biological behavior rather than independent prognostic value, highlighting the complexity of molecular regulation in renal tumorigenesis. Full article

Trastuzumab is the first humanised monoclonal antibody (Mab) developed for breast cancer (BC) therapy. The high affinity of Trastuzumab Fab-domain binding to the human epidermal growth factor receptor 2 (HER2) receptor, with a K_d value of <1 nM, is also accompanied by Fc domain interaction with Fc-receptors in natural killer cells and leukocytes, enabling the killing of tumour cells through antibody-directed cellular cytotoxicity (ADCC). Trastuzumab blocks the over-expressed HER2 receptor-mediated dimerization and consequent intracellular signalling, leading to cancerous growth. However, the trastuzumab resistance (TR) became the major problem within 1 year of treatment. The mutation in phosphatidylinositol 3′-kinase (PI3K) pathway, cross-talk with estrogen receptors, over-expression of Mucin 1 (MUC1) protein, insulin-like growth factor I receptor, etc., are key pathways involved in TR. In this review, we have provided a molecular view of TR and the possible remedies for overcoming TR using BC stem cell (BCSC)-based therapy, PI3K pathway inhibitors, MUC1-based treatment, etc. We have also analysed the patents and clinical trials from the pre-TR and post-TR era to rationalise the possible steps to overcome TR. Our analysis implies that Trastuzumab monotherapy no longer applies to HER2+ BC treatment. Further, combination therapy using other antibodies like pertuzumab and protein kinase inhibitors and targeting pathways like the ubiquitin proteasome pathway will be the future option for BC Treatment. Overall, this review provides a detailed summary of the molecular mechanisms involving TR and its potential ways of evasion, based on updated information from published research articles, clinical trial outcomes, and patent data. Full article