Acute lymphocytic leukemia (ALL) is the most common leukemia in children, with the T-cell subtype (T-ALL) accounting for 15% of those cases. Despite advancements in the treatment of T-ALL, patients still face a dismal prognosis following their first relapse. Relapse can be attributed to the inability of chemotherapy agents to eradicate leukemia stem cells (LSC), which possess self-renewal capabilities and are responsible for the long-term maintenance of the disease. Mitochondria have been recognized as a therapeutic vulnerability for cancer stem cells, including LSCs. Mitocans have shown promise in T-ALL both in vitro and in vivo, with some currently in early-phase clinical trials. However, due to challenges in studying LSCs in T-ALL, our understanding of how mitochondrial function influences self-renewal remains limited. This review highlights the emerging literature on targeting mitochondria in diverse T-ALL models, emphasizing specific mitochondrial vulnerabilities linked to LSC self-renewal and their potential to significantly improve T-ALL treatment.

Cancer stem cells (CSCs) represent a distinct subpopulation of cancer cells that orchestrate cancer initiation, progression, metastasis, and therapeutic resistance. Despite advances in conventional therapies, the persistence of CSCs remains a major obstacle to achieving cancer eradication. Nanomedicine-based approaches have emerged for precise CSC targeting and elimination, offering unique advantages in overcoming the limitations of traditional treatments. This review systematically analyzes recent developments in nanomedicine for CSC-targeted therapy, emphasizing innovative nanomaterial designs addressing CSC-specific challenges. We first provide a detailed examination of CSC biology, focusing on their surface markers, signaling networks, microenvironmental interactions, and metabolic signatures. On this basis, we critically evaluate cutting-edge nanomaterial engineering designed to exploit these CSC traits, including stimuli-responsive nanodrugs, nanocarriers for drug delivery, and multifunctional nanoplatforms capable of generating localized hyperthermia or reactive oxygen species. These sophisticated nanotherapeutic approaches enhance selectivity and efficacy in CSC elimination, potentially circumventing drug resistance and cancer recurrence. Finally, we present an in-depth analysis of current challenges in translating nanomedicine-based CSC-targeted therapies from bench to bedside, offering critical insights into future research directions and clinical implementation. This review aims to provide a comprehensive framework for understanding the intersection of nanomedicine and CSC biology, contributing to more effective cancer treatment modalities.

Splicing factor 3B (SF3B) subunit 4 (SF3B4), an SF3B complex component essential for spliceosome assembly and accurate splicing, plays a major role in cancer development. However, the precise mechanism through which SF3B4 contributes to tumor growth remains unclear. Here, we demonstrate that SF3B4 is strongly expressed in patients with various cancer types and correlated with their survival. By using hepatocellular carcinoma (HCC) as a model, we reveal that SF3B4's interactions with and regulatory influence on the checkpoint protein BUB1 are essential for appropriate cancer cell mitosis and proliferation. Our results thus demonstrate the roles of SF3B4 as both a cell-cycle regulator and an oncogenic factor in HCC, highlighting its potential as a pan-cancer therapeutic target and diagnostic biomarker.

Metastasis, the leading cause of cancer-related deaths, underscores the critical need to understand its regulatory mechanisms to improve prevention and treatment strategies for late-stage tumors. Hematogenous dissemination is a key route of metastasis. However, as the gatekeeper of vessels, the role of pericytes in hematogenous metastasis remains largely unknown. In this review, we comprehensively explore the contributions of pericytes throughout the metastatic cascade, particularly their functions that extend beyond influencing tumor angiogenesis. Pericytes should not be perceived as passive bystanders, but rather as active participants in various stages of the metastatic cascade. Pericytes-targeted therapy may provide novel insights for preventing and treating advanced-stage tumor.

Despite significant advancements in identifying novel therapeutic targets and compounds, cancer stem cells (CSCs) remain pivotal in driving therapeutic resistance and tumor progression in gastric cancer (GC). High-resolution knowledge of the transcriptional programs underlying the role of CSC niche in driving tumor stemness and progression is still lacking. Herein, spatial and single-cell RNA sequencing of 32 human gastric mucosa tissues at various stages of malignancy, illuminating the phenotypic plasticity of tumor epithelium and transcriptional trajectory from mature gastric chief cells to the CSC state, which is associated with activation of EGFR and WNT signaling pathways, is conducted. Moreover, the CSCs interact with not only the immunosuppressive CXCL13+ T cells and CCL18+ M2 macrophages to evade immune surveillance, but also the inflammatory cancer-associated fibroblasts (iCAFs) to promote tumorigenesis and maintain stemness, which construct the CSC niche leading to inferior prognosis. Notably, it is uncovered that amphiregulin (AREG) derived from iCAFs promotes tumor stemness by upregulating the expression of SOX9 in tumor cells, and contributes to drug resistance via the AREG-ERBB2 axis. This study provides valuable insight into the characteristics of CSC niche in driving tumor stemness and progression, offering novel perspective for designing effective strategies to overcome GC therapy resistance.

The components of the extracellular matrix (ECM) are dynamic, and they mediate mechanical signals that modulate cellular behaviors. Disruption of the ECM can induce the migration and invasion of cancer cells via specific signaling pathways and cytokines. Metastasis is a leading cause of high mortality in malignancies, and early intervention can improve survival rates. However, breast cancer is frequently diagnosed subsequent to metastasis, resulting in poor prognosis and distant metastasis poses substantial hurdles in therapy. In breast cancer, there is notable tissue remodeling of ECM proteins, with several identified as essential components for metastasis. Moreover, specific ECM molecules, receptors, enzymes, and various signaling pathways play crucial roles in breast cancer metastasis, drug treatment, and resistance. The in-depth consideration of these elements could provide potential therapeutic targets to enhance the survival rates and quality of life for breast cancer patients. This review explores the mechanisms by which alterations in the ECM contribute to breast cancer metastasis and discusses current clinical applications targeting ECM in breast cancer treatment, offering valuable perspectives for future ECM-based therapies.

Tumorigenesis ensues within a heterogeneous tissue microenvironment that promotes malignant transformation, metastasis and treatment resistance. A major feature of the tumor microenvironment is the heterogeneous population of cancer-associated fibroblasts and myeloid cells that stiffen the extracellular matrix. The heterogeneously stiffened extracellular matrix in turn activates cellular mechanotransduction and creates a hypoxic and metabolically hostile microenvironment. The stiffened extracellular matrix and elevated mechanosignaling also drive tumor aggression by fostering tumor cell growth, survival, and invasion, compromising antitumor immunity, expanding cancer stem cell frequency, and increasing mutational burden, which promote intratumor heterogeneity. Delineating the molecular mechanisms whereby tissue mechanics regulate these phenotypes should help to clarify the basis for tumor heterogeneity and cancer aggression and identify novel therapeutic targets that could improve patient outcome. Here, we discuss the role of the extracellular matrix in driving cancer aggression through its impact on tumor heterogeneity.

Stem cells, both normal somatic (SSC) and cancer stem cells (CSC) exist in minimally two states, i.e., quiescent and activated. Regulation of these two states, including their reliance on different metabolic processes, i.e., FAO and glycolysis in quiescent versus activated stem cells respectively, involves the analysis of a complex array of factors (nutrient and oxygen levels, adhesion molecules, cytokines, etc.) to initiate the epigenetic changes to either depart or enter quiescence. Quiescence is a critical feature of SSC that is required to maintain the genomic integrity of the stem cell pool, particularly in long lived complex organisms. Quiescence in CSC, whether they are derived from mutations arising in SSC, aberrant microenvironmental regulation, or via dedifferentiation of more committed progenitors, is a critical component of therapy resistance and disease latency and relapse. At the beginning of vertebrate evolution, approximately 450 million years ago, a gene duplication generated the two members of the Kat3 family, CREBBP (CBP) and EP300 (p300). Despite their very high degree of homology, these two Kat3 coactivators play critical and non-redundant roles at enhancers and super-enhancers via acetylation of H3K27, thereby controlling stem cell quiescence versus activation and the cells metabolic requirements. In this review/perspective, we discuss the unique regulatory roles of CBP and p300 and how specifically targeting the CBP/β-catenin interaction utilizing small molecule antagonists, can correct lineage infidelity and safely eliminate quiescent CSC.

Cellular senescence and cellular reprogramming represent two fundamentally intertwined processes that profoundly influence aging and cancer. This paper explores how the permanent cell-cycle arrest of senescent cells and the identity-resetting capacity of reprogramming jointly shape biological outcomes in later life and tumor development. We synthesize recent findings to show that senescent cells, while halting the proliferation of damaged cells, can paradoxically promote tissue dysfunction and malignancy via their secretory phenotype. Conversely, induced reprogramming of somatic cells-exemplified by Yamanaka factors-resets cellular age and epigenetic marks, offering a potential to rejuvenate aged cells. Key findings highlight shared mechanisms (e.g., DNA damage responses and epigenetic remodeling) and bidirectional crosstalk between these processes: senescence signals can facilitate neighboring cell plasticity, whereas reprogramming attempts can trigger intrinsic senescence programs as a barrier. In aging tissues, transient (partial) reprogramming has been shown to erase senescence markers and restore cell function without inducing tumorigenesis, underlining a novel strategy to combat age-related degeneration. In cancer, we discuss how therapy-induced senescence of tumor cells may induce stem-cell-like traits in some cells and drive relapse, revealing a delicate balance between tumor suppression and tumor promotion. Understanding the interplay between senescence and reprogramming is crucial for developing innovative therapies. By targeting the senescence-reprogramming axis-for instance, via senolytic drugs, SASP inhibitors, or safe reprogramming techniques-there is significant therapeutic potential to ameliorate aging-related diseases and improve cancer treatment. Our findings underscore that carefully modulating cellular senescence and rejuvenation processes could pave the way for novel regenerative and anti-cancer strategies.

Over the last 2 decades, research has increasingly focused on cancer stem cells (CSCs), considered responsible for tumor formation, resistance to therapies, and relapse. The traditional "static" CSC model used to describe tumor heterogeneity has been challenged by the evidence of CSC dynamic nature and plasticity. A comprehensive understanding of the mechanisms underlying this plasticity, and the capacity to unambiguously identify cancer markers to precisely target CSCs are crucial aspects for advancing cancer research and introducing more effective treatment strategies. In this context, Raman spectroscopy (RS) and specific Raman schemes, including CARS, SRS, SERS, have emerged as innovative tools for molecular analyses both in vitro and in vivo. In fact, these techniques have demonstrated considerable potential in the field of cancer detection, as well as in intraoperative settings, thanks to their label-free nature and minimal invasiveness. However, the RS integration in pre-clinical and clinical applications, particularly in the CSC field, remains limited. This review provides a concise overview of the historical development of RS and its advantages. Then, after introducing the CSC features and the challenges in targeting them with traditional methods, we review and discuss the current literature about the application of RS for revealing and characterizing CSCs and their inherent plasticity, including a brief paragraph about the integration of artificial intelligence with RS. By providing the possibility to better characterize the cellular diversity in their microenvironment, RS could revolutionize current diagnostic and therapeutic approaches, enabling early identification of CSCs and facilitating the development of personalized treatment strategies.

Metabolic reprogramming enables tumour cells to sustain their continuous proliferation and adapt to the ever-changing microenvironment. Branched-chain amino acids (BCAAs) and their metabolites are involved in intracellular protein synthesis and catabolism, signal transduction, epigenetic modifications, and the maintenance of oxidative homeostasis. Alterations in BCAA metabolism can influence the progression of various tumours. However, how BCAA metabolism is dysregulated differs among depending on tumour type; for example, it can manifest as decreased BCAA metabolism leading to BCAA accumulation, or as enhanced BCAA uptake and increased catabolism. In this review, we describe the role of BCAA metabolism in the progression of different tumours. As well as discuss how BCAA metabolic reprogramming drives tumour therapy resistance and evasion of the antitumour immune response, and how these pro-cancer effects are achieved in part by activating the mTORC signalling pathway. In-depth investigations into the potential mechanisms by which BCAA metabolic reprogramming affects tumorigenesis and tumour progression can enhance our understanding of the relationship between metabolism and cancer and provide new strategies for cancer therapy.

Stem cells have emerged as a pivotal area of research in the field of oncology, offering new insights into the mechanisms of cancer initiation, progression, and resistance to therapy. This review provides a comprehensive overview of the role of stem cells in cancer, focusing on cancer stem cells (CSCs), their characteristics, and their implications for cancer therapy. We discuss the origin and identification of CSCs, their role in tumorigenesis, metastasis, and drug resistance, and the potential therapeutic strategies targeting CSCs. Additionally, we explore the use of normal stem cells in cancer therapy, focusing on their role in tissue regeneration and their use as delivery vehicles for anticancer agents. Finally, we highlight the challenges and future directions in stem cell research in cancer.

The acidic tumor microenvironment (TME) favors cancer aggressiveness via incompletely understood pathways. Here, we asked whether adaptation to environmental acidosis (pH 6.5) selects for human pancreatic cancer stem cell (CSC) properties. RNA sequencing (RNA-seq) of acid-adapted (AA) Panc-1 cells revealed CSC pathway enrichment and upregulation of CSC markers. AA Panc-1 cells exhibited classical CSC characteristics including increased aldehyde dehydrogenase (ALDH) activity and β-catenin activity. Panc-1, PaTu8988s, and MiaPaCa-2 cells all exhibited increased pancreatosphere-forming efficiency after acid adaptation but differed in CSC marker expression and did not exhibit typical flow cytometric CSC populations. However, single-nucleus sequencing revealed the acid adaptation-induced emergence of Panc-1 cell subpopulations with clear CSC characteristics. In orthotopic mouse tumors, AA Panc-1 cells exhibited enhanced aggressiveness, liver and lung metastasis, compared to controls. Collectively, our work suggests that acid adaptation enriches for pancreatic CSC phenotypes with unusual traits via several trajectories, providing new insight into how acidic microenvironments favor cancer aggressiveness.

In the domain of addressing cancer resistance, challenges such as limited effectiveness and treatment resistance remain persistent. Hypoxia is a key feature of solid tumors and is strongly associated with poor prognosis in cancer patients. Another significant portion of the development of acquired drug resistance is attributed to tumor stemness. Cancer stem cells (CSCs), a small tumor cell subset with self-renewal and proliferative abilities, are crucial for tumor initiation, metastasis, and intra-tumoral heterogeneity. Studies have shown a significant association between hypoxia and CSCs in the context of tumor resistance. Recent studies reveal a strong link between hypoxia and tumor stemness, which together promote tumor survival and progression during treatment. This review elucidates the interplay between hypoxia and CSCs, as well as their correlation with resistance to therapeutic drugs. Targeting pivotal genes associated with hypoxia and stemness holds promise for the development of novel therapeutics to combat tumor resistance.

Recent breakthroughs in tumor immunotherapy have confirmed the capacity of the immune system to fight several cancers. The effective means of treating cancer involves accelerating the death of tumor cells and improving patient immunity. Dynamic changes in the tumor immune microenvironment alter the actual effects of anti-tumor drug production and may trigger favorable or unfavorable immune responses by modulating tumor-infiltrating lymphocytes. Notably, CD8+ T cells are one of the primary tumor-infiltrating immune cells that provide anti-tumor response. Tumor cells and tumor stem cells will resist or evade destruction through various mechanisms as CD8+ T cells exert their anti-tumor function. This paper reviews the research on the regulation of tumor development and prognosis by cancer stem cells that directly or indirectly alter the role of tumor-infiltrating CD8+ T cells. We also discuss related immunotherapy strategies.

Breast cancer stem cells are a promising therapeutic target in cancer. We explored breast cancer stem cell diversity and establish a methodology for selectively culturing breast cancer stem cells. We collected breast cancer tissues from surgical samples of treatment-naïve patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Following isolation, cells were subjected to spheroid culture on non-adherent plates. Of the 57 cases, successful culture was achieved in 48 cases, among which the average ratio of CD44+/CD24- breast cancer cells increased from 13.8% in primary tumors to 61.6% in spheroids. A modest number of spheroid cells successfully engrafted in mice and subsequently re-differentiated within the murine environment, confirming their stemness. ER expression in spheroid cells exhibited negative conversion in 52.1% of cases. The proportion of Twist-, Snail-, and Vimentin-positive cells increased from 43.8%, 12.9%, and 7.7-75.0%, 58.1%, and 37.7%, respectively. ER-positive, HER2-negative breast cancer stem cells were classified into two groups using DNA microarrays. Gene Ontology analysis unveiled higher expression of immune response-related genes in one group and protein binding-associated genes in the other. We demonstrated stable and selective culture of breast cancer stem cells from patient-derived breast cancer tissue using spheroid cultures.

Glioblastoma is the most common primary malignant brain tumor in adults, with a median survival of just over 1 year. The failure of available treatments to achieve remission in patients with glioblastoma (GBM) has been attributed to the presence of cancer stem cells (CSCs), which are thought to play a central role in tumor development and progression and serve as a treatment-resistant cell repository capable of driving tumor recurrence. In fact, the property of "stemness" itself may be responsible for treatment resistance. In this study, we identify a novel long noncoding RNA (lncRNA), cancer stem cell-associated distal enhancer of SOX2 (CASCADES), that functions as an epigenetic regulator in glioma CSCs (GSCs). CASCADES is expressed in isocitrate dehydrogenase (IDH)-wild-type GBM and is significantly enriched in GSCs. Knockdown of CASCADES in GSCs results in differentiation towards a neuronal lineage in a cell- and cancer-specific manner. Bioinformatics analysis reveals that CASCADES functions as a super-enhancer-associated lncRNA epigenetic regulator of SOX2. Our findings identify CASCADES as a critical regulator of stemness in GSCs that represents a novel epigenetic and therapeutic target for disrupting the CSC compartment in glioblastoma.

Cell plasticity emerges as a novel cancer hallmark and is pivotal in driving tumor heterogeneity and adaptive resistance to different therapies. Cancer stem-like cells (CSCs) are considered the root of cancer. While first defined as tumor-initiating cells with the potential to develop a heterogeneous tumor, CSCs further demonstrate their roles in cancer metastasis and adaptive therapeutic resistance. Generally, CSCs come from the malignant transformation of somatic stem cells or the de-differentiation of other cancer cells. The resultant cells gain more plasticity and are ready to differentiate into different cell states, enabling them to adapt to therapies and metastatic ecosystems. Therefore, CSCs are likely the nature of tumor cells that gain cell plasticity. However, the phenotypic plasticity of CSCs has never been systematically discussed. Here, we review the distinct intrinsic signaling pathways and unique microenvironmental niches that endow CSC plasticity in solid tumors to adapt to stressful conditions, as well as emerging opportunities for CSC-targeted therapy.

Pediatric glioblastoma is a complex dynamical disease that is difficult to treat due to its multiple adaptive behaviors driven largely by phenotypic plasticity. Integrated data science and network theory pipelines offer novel approaches to studying glioblastoma cell fate dynamics, particularly phenotypic transitions over time. Here we used various single-cell trajectory inference algorithms to infer signaling dynamics regulating pediatric glioblastoma-immune cell networks. We identified GATA2, PTPRZ1, TPT1, MTRNR2L1/2, OLIG1/2, SOX11, FXYD6, SEZ6L, PDGFRA, EGFR, S100B, WNT, TNF α , and NF-kB as critical transition genes or signals regulating glioblastoma-immune network dynamics, revealing potential clinically relevant targets. Further, we reconstructed glioblastoma cell fate attractors and found complex bifurcation dynamics within glioblastoma phenotypic transitions, suggesting that a causal pattern may be driving glioblastoma evolution and cell fate decision-making. Together, our findings have implications for developing targeted therapies against glioblastoma, and the continued integration of quantitative approaches and artificial intelligence (AI) to understand pediatric glioblastoma tumor-immune interactions.

Cancer is a heterogeneous disease, which contributes to its rapid progression and therapeutic failure. Besides interpatient tumor heterogeneity, tumors within a single patient can present with a heterogeneous mix of genetically and phenotypically distinct subclones. These unique subclones can significantly impact the traits of cancer. With the plasticity that intratumoral heterogeneity provides, cancers can easily adapt to changes in their microenvironment and therapeutic exposure. Indeed, tumor cells dynamically shift between a more differentiated, rapidly proliferating state with limited tumorigenic potential and a cancer stem cell (CSC)-like state that resembles undifferentiated cellular precursors and is associated with high tumorigenicity. In this context, CSCs are functionally located at the apex of the tumor hierarchy, contributing to the initiation, maintenance, and progression of tumors, as they also represent the subpopulation of tumor cells most resistant to conventional anti-cancer therapies. Although the CSC model is well established, it is constantly evolving and being reshaped by advancing knowledge on the roles of CSCs in different cancer types. Here, we review the current evidence of how CSCs play a pivotal role in providing the many traits of aggressive tumors while simultaneously evading immunosurveillance and anti-cancer therapy in several cancer types. We discuss the key traits and characteristics of CSCs to provide updated insights into CSC biology and highlight its implications for therapeutic development and improved treatment of aggressive cancers.

Glioblastoma (GBM) remains a formidable clinical challenge, with cancer stem cells (CSCs) contributing to treatment resistance and tumor recurrence. Conventional treatments often fail to eradicate these CSCs characterized by enhanced resistance to standard therapies through metabolic plasticity making them key targets for novel treatment approaches. Addressing this challenge, this study introduces a novel combination therapy of dichloroacetate (DCA), a metabolic modulator and nonthermal plasma to induce oxidative stress in glioblastomas. Our results demonstrate that DCA and nonthermal plasma (NTP) synergistically increase ROS production, resulting in endoplasmic reticulum (ER) stress and mitochondrial reprogramming, key factors in the initiation of programmed cell death. Furthermore, the combination downregulated key stemness markers indicating effective CSCs suppression. Upregulation of pro-apoptotic proteins and downregulation of anti-apoptotic factors highlight the induction of apoptosis in glioma stem cells. This study provides compelling evidence that the combination of DCA and NTP offers a novel and effective strategy for targeting glioma CSCs by inducing oxidative and metabolic stress, underscoring potential therapeutic advancements in glioblastoma treatment.

Cancer stem cells (CSCs) are central to tumor progression, metastasis, immune evasion, and therapeutic resistance. Characterized by remarkable self-renewal and adaptability, CSCs can transition dynamically between stem-like and differentiated states in response to external stimuli, a process termed "CSC plasticity." This adaptability underpins their resilience to therapies, including immune checkpoint inhibitors and adoptive cell therapies (ACT). Beyond intrinsic properties, CSCs reside in a specialized microenvironment-the CSC niche-which provides immune-privileged protection, sustains their stemness, and fosters immune suppression. This review highlights the critical role of CSCs and their niche in driving immunotherapy resistance, emphasizing the need for integrative approaches to overcome these challenges.

The progression of malignant tumors leads to the development of secondary tumors in various organs, including bones, the brain, liver, and lungs. This metastatic process severely impacts the prognosis of patients, significantly affecting their quality of life and survival rates. Research efforts have consistently focused on the intricate mechanisms underlying this process and the corresponding clinical management strategies. Consequently, a comprehensive understanding of the biological foundations of tumor metastasis, identification of pivotal signaling pathways, and systematic evaluation of existing and emerging therapeutic strategies are paramount to enhancing the overall diagnostic and treatment capabilities for metastatic tumors. However, current research is primarily focused on metastasis within specific cancer types, leaving significant gaps in our understanding of the complex metastatic cascade, organ-specific tropism mechanisms, and the development of targeted treatments. In this study, we examine the sequential processes of tumor metastasis, elucidate the underlying mechanisms driving organ-tropic metastasis, and systematically analyze therapeutic strategies for metastatic tumors, including those tailored to specific organ involvement. Subsequently, we synthesize the most recent advances in emerging therapeutic technologies for tumor metastasis and analyze the challenges and opportunities encountered in clinical research pertaining to bone metastasis. Our objective is to offer insights that can inform future research and clinical practice in this crucial field.

Oral squamous cell carcinoma (OSCC) remains a major cause of morbidity and mortality worldwide with high recurrence rates and resistance to conventional therapies. Recent studies have highlighted the pivotal role of oral cancer stem cells (OCSCs) in driving treatment resistance and tumor recurrence. OCSCs possess unique properties, including self-renewal, differentiation potential, and resistance to chemotherapy and radiotherapy, which contribute to their ability to survive treatment and initiate tumor relapse. Several signaling pathways, such as Wnt/β-catenin, Hedgehog, Notch, and PI3K/Akt/mTOR, have been implicated in maintaining OCSC properties, promoting survival, and conferring resistance. Additionally, mechanisms such as drug efflux, enhanced DNA repair, epithelial-mesenchymal transition (EMT), and resistance to apoptosis further contribute to resilience. Targeting these pathways offers promising therapeutic strategies for eliminating OCSCs and improving treatment outcomes. Approaches such as immunotherapy, nanotechnology-based drug delivery, and targeting of the tumor microenvironment are emerging as potential solutions to overcome OCSC-mediated resistance. However, further research is needed to fully understand the molecular mechanisms governing OCSCs and develop effective therapies to prevent tumor recurrence. This review discusses the role of OCSCs in treatment resistance and recurrence and highlights the current and future directions for targeting these cells in OSCC.

Oral cancer, a subtype of head and neck cancer, poses significant global health challenges owing to its late diagnosis and high metastatic potential. The epithelial cell adhesion molecule (EpCAM), a transmembrane glycoprotein, has emerged as a critical player in cancer biology, particularly in oral cancer stem cells (CSCs). This review highlights the multifaceted roles of EPCAM in regulating oral cancer metastasis, tumorigenicity, and resistance to therapy. EpCAM influences key pathways, including Wnt/β-catenin and EGFR, modulating CSC self-renewal, epithelial-to-mesenchymal transition (EMT), and immune evasion. Moreover, EpCAM has been implicated in metabolic reprogramming, epigenetic regulation, and crosstalk with other signaling pathways. Advances in EpCAM-targeting strategies, such as monoclonal antibodies, chimeric antigen receptor (CAR) T/NK cell therapies, and aptamer-based systems hold promise for personalized cancer therapies. However, challenges remain in understanding the precise mechanism of EpCAM in CSC biology and its translation into clinical applications. This review highlights the need for further investigation into the role of EPCAM in oral CSCs and its potential as a therapeutic target to improve patient outcomes.

Cancer stem cells (CSCs) are a small subset within the tumor mass significantly contributing to cancer progression through dysregulation of various oncogenic pathways, driving tumor growth, chemoresistance and metastasis formation. The aggressive behavior of CSCs is guided by several intracellular signaling pathways such as WNT, NF-kappa-B, NOTCH, Hedgehog, JAK-STAT, PI3K/AKT1/MTOR, TGF/SMAD, PPAR and MAPK kinases, as well as extracellular vesicles such as exosomes, and extracellular signaling molecules such as cytokines, chemokines, pro-angiogenetic and growth factors, which finely regulate CSC phenotype. In this scenario, tumor microenvironment (TME) is a key player in the establishment of a permissive tumor niche, where CSCs engage in intricate communications with diverse immune cells. The "oncogenic" immune cells are mainly represented by B and T lymphocytes, NK cells, and dendritic cells. Among immune cells, macrophages exhibit a more plastic and adaptable phenotype due to their different subpopulations, which are characterized by both immunosuppressive and inflammatory phenotypes. Specifically, tumor-associated macrophages (TAMs) create an immunosuppressive milieu through the production of a plethora of paracrine factors (IL-6, IL-12, TNF-alpha, TGF-beta, CCL1, CCL18) promoting the acquisition by CSCs of a stem-like, invasive and metastatic phenotype. TAMs have demonstrated the ability to communicate with CSCs via direct ligand/receptor (such as CD90/CD11b, LSECtin/BTN3A3, EPHA4/Ephrin) interaction. On the other hand, CSCs exhibited their capacity to influence immune cells, creating a favorable microenvironment for cancer progression. Interestingly, the bidirectional influence of CSCs and TME leads to an epigenetic reprogramming which sustains malignant transformation. Nowadays, the integration of biological and computational data obtained by cutting-edge technologies (single-cell RNA sequencing, spatial transcriptomics, trajectory analysis) has significantly improved the comprehension of the biunivocal multicellular dialogue, providing a comprehensive view of the heterogeneity and dynamics of CSCs, and uncovering alternative mechanisms of immune evasion and therapeutic resistance. Moreover, the combination of biology and computational data will lead to the development of innovative target therapies dampening CSC-TME interaction. Here, we aim to elucidate the most recent insights on CSCs biology and their complex interactions with TME immune cells, specifically TAMs, tracing an exhaustive scenario from the primary tumor to metastasis formation.

Tumor metabolism is crucial in the continuous advancement and complex growth of cancer. The emerging field of nanotechnology has made significant strides in enhancing the understanding of the complex metabolic intricacies inherent to tumors, offering potential avenues for their strategic manipulation to achieve therapeutic goals. This comprehensive review delves into the interplay between tumor metabolism and various facets of cancer, encompassing its origins, progression, and the formidable challenges posed by metastasis. Simultaneously, it underscores the classification of programmable nanomodulators and their transformative impact on enhancing cancer treatment, particularly when integrated with modalities such as chemotherapy, radiotherapy, and immunotherapy. This review also encapsulates the mechanisms by which nanomodulators modulate tumor metabolism, including the delivery of metabolic inhibitors, regulation of oxidative stress, pH value modulation, nanoenzyme catalysis, nutrient deprivation, and RNA interference technology, among others. Additionally, the review delves into the prospects and challenges of nanomodulators in clinical applications. Finally, the innovative concept of using nanomodulators to reprogram metabolic pathways is introduced, aiming to transform cancer cells back into normal cells. This review underscores the profound impact that tailored nanomodulators can have on tumor metabolic, charting a path toward pioneering precision therapies for cancer.

Accumulating evidence supports the idea that cancer stem cells (CSCs) are those with the capacity to initiate tumors, generate phenotypical diversity, sustain growth, confer drug resistance, and orchestrate the spread of tumor cells. It is still controversial whether CSCs originate from normal stem cells residing in the tissue or cancer cells from the tumor bulk that have dedifferentiated to acquire stem-like characteristics. Although CSCs have been pointed out as key drivers in cancer, knowledge regarding their physiology is still blurry; thus, research focusing on CSCs is essential to designing novel and more effective therapeutics. The purinergic system has emerged as an important autocrine-paracrine messenger system with a prominent role at multiple levels of the tumor microenvironment, where it regulates cellular aspects of the tumors themselves and the stromal and immune systems. Recent findings have shown that purinergic signaling also participates in regulating the CSC phenotype. Here, we discuss updated information regarding CSCs in the purinergic system and present evidence supporting the idea that elements of the purinergic system expressed by this subpopulation of the tumor represent attractive pharmacological targets for proposing innovative anti-cancer therapies.

The problem of treating cancer patients with lung cancer has become more difficult due to the SARS-CoV-2 viral infection and concomitant bacterial lesions. The analysis shows that the photodynamic effect of long-wavelength polycationic photosensitizers suppresses the tumor process (including the destruction of cancer stem cells), SARS-CoV-2 coronavirus infection, Gram-positive and Gram-negative bacteria, including those that can cause pneumonia. Therefore, the photodynamic approach using such photosensitizers is promising for the development of an effective treatment method for patients with lung cancer, including those with SARS-CoV-2 infection and bacterial complications.

Stemness, giving cancer cells massive plasticity enabling them to survive in dynamic (e.g. hypoxic) environments and become resistant to treatment, especially chemotherapy, is an important property of aggressive tumours. Here, we review some essentials of cancer stemness focusing on triple-negative breast cancer (TNBC), the most aggressive form of all breast cancers. TNBC cells express a range of genes and mechanisms associated with stemness, including the fundamental four "Yamanaka factors". Most of the evidence concerns the transcription factor / oncogene c-Myc and an interesting case is the expression of the neonatal splice variant of voltage-gated sodium channel subtype Nav1.5. On the whole, measures that reduce the stemness make cancer cells less aggressive, reducing their invasive/metastatic potential and increasing/restoring their chemosensitivity. Such measures include gene silencing techniques, epigenetic therapies as well as novel approaches like optogenetics aiming to modulate the plasma membrane voltage. Indeed, simply hyperpolarizing their membrane potential can make stem cells differentiate. Finally, we give an overview of the clinical aspects and exploitation of cancer/TNBC stemness, including diagnostics and therapeutics. In particular, personalised mRNA-based therapies and mechanistically meaningful combinations are promising and the emerging discipline of 'cancer neuroscience' is providing novel insights to both fundamental issues and clinical applications.

Cancer stem cells (CSCs) typically reside in perivascular niches, but whether endothelial cells of blood vessels influence the stemness of cancer cells remains poorly understood. This study revealed that endothelial cell-specific GLTSCR1 deletion promotes colorectal cancer (CRC) tumorigenesis and metastasis by increasing cancer cell stemness. Mechanistically, knocking down GLTSCR1 induces the transformation of endothelial cells into tip cells by regulating the expression of Neuropilin-1 (NRP1), thereby increasing the direct contact and interaction between endothelial cells and tumour cells. In addition, GLTSCR1 inhibits JAG1 transcription by competing with acetylated p65(Lys-310) to bind to the BRD4 interaction site. Therefore, GLTSCR1 deficiency increases JAG1 expression in endothelial cells. Subsequently, increased JAG1 levels on tip cell membranes bind to Notch on CRC cell membranes, activating the Notch signalling pathway in tumour cells and increasing CRC cell stemness. Taken together, our findings highlight the roles of endothelial cells in CRC development.

Cancer stem cells (CSCs) play a central role in tumor progression, recurrence, and resistance to conventional therapies, making them a critical focus in oncology research. This review provides a comprehensive analysis of CSC biology, emphasizing their self-renewal, differentiation, and dynamic interactions with the tumor microenvironment (TME). Key signaling pathways, including Wnt, Notch, and Hedgehog, are discussed in detail to highlight their potential as therapeutic targets. Current methodologies for isolating CSCs are critically examined, addressing their advantages and limitations in advancing precision medicine. Emerging technologies, such as CRISPR/Cas9 and single-cell sequencing, are explored for their transformative potential in unraveling CSC heterogeneity and informing therapeutic strategies. The review also underscores the pivotal role of the TME in supporting CSC survival, promoting metastasis, and contributing to therapeutic resistance. Challenges arising from CSC-driven tumor heterogeneity and dormancy are analyzed, along with strategies to mitigate these barriers, including novel therapeutics and targeted approaches. Ethical considerations and the integration of artificial intelligence in designing CSC-specific therapies are discussed as essential elements of future research. The manuscript advocates for a multi-disciplinary approach that combines innovative technologies, advanced therapeutics, and collaborative research to address the complexities of CSCs. By bridging existing gaps in knowledge and fostering advancements in personalized medicine, this review aims to guide the development of more effective cancer treatment strategies, ultimately improving patient outcomes.

Oncogenes are typically overexpressed in tumor tissues and often linked to poor prognosis. However, recent advancements in bioinformatics have revealed that many highly expressed genes in tumors are associated with better patient outcomes. These genes, which act as tumor suppressors, are referred to as "paradoxical genes." Analyzing The Cancer Genome Atlas (TCGA) confirmed the widespread presence of paradoxical genes, and KEGG analysis revealed their role in regulating tumor metabolism. Mechanistically, discrepancies between gene and protein expression-affected by pre- and post-transcriptional modifications-may drive this phenomenon. Mechanisms like upstream open reading frames and alternative splicing contribute to these inconsistencies. Many paradoxical genes modulate the tumor immune microenvironment, exerting tumor-suppressive effects. Further analysis shows that the stage- and tumor-specific expression of these genes, along with their environmental sensitivity, influence their dual roles in various signaling pathways. These findings highlight the importance of paradoxical genes in resisting tumor progression and maintaining cellular homeostasis, offering new avenues for targeted cancer therapy.

Breast cancer stem-like cells (CSCs) are enriched following treatment with chemotherapy, and posited as having a high level of plasticity and enhanced tumor-initiation capacity, which can enable cancer relapse. Here, we show that such features are shared by breast cancer (BCA) cells that express receptor tyrosine kinase-like orphan receptor (ROR2), which is expressed primarily during embryogenesis and by various cancers. We find that Wnt5a can induce ROR2 homooligomerization to activate noncanonical Wnt signaling and enhance tumor-initiation capacity of BCA cells. Molecular analysis reveals that the cysteine-rich domain and transmembrane domain are required for ROR2 homooligomerization to activate ROR2. Treatment with a newly generated monoclonal antibody (mAb) specific for ROR2 can block Wnt5a-induced ROR2 homooligomerization, ROR2-dependent noncanonical Wnt signaling, and impair the capacity of BCA patient-derived xenografts to initiate tumor in immune-deficient mice. Collectively, these results indicate that targeting ROR2 (e.g., using mAb) suppresses BCA stemness and, thereby, may prevent BCA relapse.

Cancer stem cells (CSC) are known to be the main source of tumor relapse, metastasis, or multidrug resistance and the mechanisms to counteract or eradicate them and their activity remain elusive. There are different hypotheses that claim that the origin of CSC might be in regular stem cells (SC) and, due to accumulation of mutations, these normal cells become malignant, or the source of CSC might be in any malignant cell that, under certain environmental circumstances, acquires all the qualities to become CSC. Multiple studies indicate that lifestyle and diet might represent a source of wellbeing that can prevent and ameliorate the malignant phenotype of CSC. In this review, after a brief introduction to SC and CSC, we analyze the effects of phenolic and non-phenolic dietary compounds and we highlight the molecular mechanisms that are shown to link diets to CSC activation in colon, breast, and prostate cancer. We focus the analysis on specific markers such as sphere formation, CD surface markers, epithelial-mesenchymal transition (EMT), Oct4, Nanog, Sox2, and aldehyde dehydrogenase 1 (ALDH1) and on the major signaling pathways such as PI3K/Akt/mTOR, NF-κB, Notch, Hedgehog, and Wnt/β-catenin in CSC. In conclusion, a better understanding of how bioactive compounds in our diets influence the dynamics of CSC can raise valuable awareness towards reducing cancer risk.

Cancer stem cells (CSCs) often exhibit stem-like attributes that depend on an intricate stemness-promoting cellular ecosystem within their niche. The interplay between CSCs and their niche has been implicated in tumor heterogeneity and therapeutic resistance. Normal stem cells (NSCs) and CSCs share stemness features and common microenvironmental components, displaying significant phenotypic and functional plasticity. Investigating these properties across diverse organs during normal development and tumorigenesis is of paramount research interest and translational potential. Advancements in next-generation sequencing (NGS), single-cell transcriptomics, and spatial transcriptomics have ushered in a new era in cancer research, providing high-resolution and comprehensive molecular maps of diseased tissues. Various spatial technologies, with their unique ability to measure the location and molecular profile of a cell within tissue, have enabled studies on intratumoral architecture and cellular cross-talk within the specific niches. Moreover, delineation of spatial patterns for niche-specific properties such as hypoxia, glucose deprivation, and other microenvironmental remodeling are revealed through multilevel spatial sequencing. This tremendous progress in technology has also been paired with the advent of computational tools to mitigate technology-specific bottlenecks. Here we discuss how different spatial technologies are used to identify NSCs and CSCs, as well as their associated niches. Additionally, by exploring related public data sets, we review the current challenges in characterizing such niches, which are often hindered by technological limitations, and the computational solutions used to address them.

In recent years, nano-drug delivery systems (Nano-DDS) that target the tumor microenvironment (TME) to overcome multidrug resistance (MDR) have become a research hotspot in the field of cancer therapy. By precisely targeting the TME and regulating its unique pathological features, such as hypoxia, weakly acidic pH, and abnormally expressed proteins, etc., these Nano-DDS enable effective delivery of therapeutic agents and reversal of MDR. This scientific research community is increasing its investment in the development of diversified systems and exploring their anti-drug resistance potential. Therefore, it is particularly important to conduct a comprehensive review of the research progress of TME-targeted Nano-DDS in recent years. After a brief introduction of TME and tumor MDR, the design principle and structure of liposomes, polymer micelles and inorganic nanocarriers are focused on, and their characteristics as TME-targeted nanocarriers are described. It also demonstrates how these systems break through the cancer MDR treatment through various targeting mechanisms, discusses their synthetic innovation, research results and resistance overcoming mechanisms. The review was concluded with deliberations on the key challenges and future outlooks of targeting TME Nano-DDS in cancer therapy.