ABSTRACT Early‐onset colorectal cancer (EOCRC) is increasing worldwide, yet the molecular basis underlying its age‐related heterogeneity remains insufficiently defined. To address this gap, we performed whole‐exome sequencing in a Chinese EOCRC cohort diagnosed before 40 years of age ( n = 111), bulk transcriptome sequencing in a subset of these tumors ( n = 59), and whole‐exome sequencing in an independent Chinese colorectal cancer cohort spanning a broader age range ( n = 210). We then integrated these data with publicly available somatic mutation, bulk RNA‐seq, and single‐cell transcriptomic datasets to characterize age‐associated tumor‐intrinsic and microenvironmental features. Genomic analyses revealed a distinct EOCRC landscape, including lower frequencies of APC and KRAS mutations, more frequent SMAD4 disruption through mutation or copy‐number loss, and enrichment of the PTPRK‐RSPO3 fusion. Single‐cell analyses further showed increased infiltration of CD4 + memory T cells and mast cells in EOCRC, whereas later‐onset colorectal cancer was characterized by SPP1 + macrophage predominance and a strengthened interaction axis between FAP + cancer‐associated fibroblasts and SPP1 + macrophages. Therapeutic evaluation in aged mouse models, together with single‐cell analysis of immunotherapy‐treated patients, indicated reduced PD‐1 blockade efficacy with increasing age. Together, these findings support age‐informed molecular classification and therapeutic stratification in colorectal cancer.
ABSTRACT Nitric oxide (NO) is an endogenous gasotransmitter that influences cancer progression in a concentration‐dependent manner, acting as either a tumor promoter or suppressor. Although this dual role is recognized, an integrated framework systematically linking its molecular mechanisms, immunomodulatory functions, and therapeutic translation is lacking, limiting rational design of NO‐based anticancer interventions. This review analyzes the molecular basis of the concentration‐dependent biphasic effects of NO, spanning canonical soluble guanylate cyclase‐cyclic guanosine monophosphate (cGMP) signaling, protein S‐nitrosylation (SNO), and peroxynitrite‐driven nitrosative stress. It then examines how these signaling pathways drive the direct effects of NO on tumor cell proliferation, metabolism, angiogenesis, and therapy resistance. It further delineates how these effects, together with NO‐mediated immunomodulation, define a dual role that encompasses both tumor cell‐intrinsic processes and antitumor immunity across innate and adaptive compartments. The therapeutic translation of these mechanistic insights is examined through NO donor chemistry and the integration of such donors into stimulus‐responsive delivery platforms, molecular conjugates, and combination regimens pairing NO with chemotherapy, radiotherapy, and immunotherapy. By connecting fundamental NO biology with emerging therapeutic strategies, this review offers an integrated framework to guide development of spatiotemporally controlled NO‐based interventions and identifies translational bottlenecks requiring resolution for clinical application, including targeted delivery, controlled release kinetics, and context‐dependent therapeutic windows.
ABSTRACT Evidence is limited on long‐term prognosis, and little is known about the immunotranscriptome in esophageal squamous cell carcinoma (ESCC) patients with different tumor regression grades (TRGs) after neoadjuvant chemoradiotherapy (NCRT) followed by surgery. Herein, the prognostic analysis of 300 ESCC patients treated with NCRT and surgery revealed that the TRG0/1 group (good responders) had significantly longer disease‐free survival (DFS) and overall survival (OS) than the TRG2/3 group. Integrating TRG and pathological N‐stage, we developed a tumor regression grade and lymph node (TRGN) staging system, which demonstrated superior prognostic stratification and distinct recurrence patterns. Transcriptome analysis showed that compared to the TRG2/3 group, the TRG0/1 group exhibited higher scores in immune checkpoint blockade (ICB) response‐related signatures, greater similarity to ICB responder samples, and increased T‐cell receptor clonality, suggesting enhanced immunotherapy sensitivity. Integrating scRNA‐seq and RNA‐seq, we identified B cell, CD8+ T cell, and NK cell subsets associated with better NCRT responses, within which a tight cell communication network potentially mediating antitumor immunity was formed. Multiplexed immunohistochemistry confirmed that the spatial relationship between CD8+ T/NK cells and tumor cells improved the NCRT response. These findings confirmed the prognostic value of TRGs and can help guide surveillance and treatment strategies in ESCC.
Triple-negative breast cancer (TNBC) poses a major challenge in women's health due to its aggressive nature and lack of targeted therapies. beta-Elemene, a sesquiterpene derived from Curcuma wenyujin, has shown clinical benefits in TNBC, but its mechanisms of action, particularly regarding the immune and metabolic tumor microenvironment, are still poorly defined. In this study, we employed single-cell RNA sequencing and untargeted metabolomics to investigate how beta-elemene reshapes the cellular and metabolic landscape of TNBC in a 4T1 orthotopic mouse model. Our results revealed that beta-elemene inhibited both primary tumor development and pulmonary metastasis in TNBC. Single-cell analysis identified 11 distinct cell subpopulations, with cancer-associated fibroblasts (CAFs) showing the most pronounced reduction upon beta-elemene treatment. Further mechanistic studies indicated that beta-elemene enhanced antigen presentation in tumor cells while suppressing CAF-mediated extracellular matrix remodeling and focal adhesion, thereby disrupting their pro-tumorigenic cellular communication. Additionally, metabolomic profiling revealed a significant downregulation of prostaglandins, including PGH2, PGF2 alpha, PGD2, and PGE2 in the arachidonic acid metabolism pathway, which was critically implicated in immune regulation. The above findings would provide the first comprehensive elucidation of beta-elemene's dual immunomodulatory and metabolic effects in TNBC, underscoring the potential of natural compounds to augment antitumor immunity.
Colorectal cancer (CRC) progression and therapeutic resistance are largely driven by the persistence of cancer stem-like cells (CSCs) and an immunosuppressive tumor microenvironment (TME). Current therapies often fail to address these two factors simultaneously, limiting their clinical efficacy. In this study, we developed a zinc-coordination-driven nanoplatform (CS/ZIF-8@MIT-ALA, "CNPs") designed to simultaneously ablate CSCs and polarize the TME toward an immunostimulatory state. This CD44-targeted nanoassembly was fabricated by loading a mitoxantrone-5-aminolevulinic acid (MIT-ALA) conjugate into a ZIF-8 framework, subsequently encapsulated with chondroitin sulfate (CS). CNPs exhibited precise pH-responsive drug release and superior tumor-targeting capabilities. In vitro, the synergistic release of Zn2+ and ALA disrupted glucose metabolism and mitochondrial integrity, thereby effectively suppressing CSC-associated stemness and triggering gasdermin D (GSDMD)-mediated pyroptosis. In vivo, CNPs effectively inhibited tumor growth and promoted a pronounced "cold-to-hot" tumor transition, as evidenced by enhanced immune cell infiltration and activation. Mechanistically, the integration of metabolic reprogramming with pyroptosis induction amplified antitumor immunity and improved chemo-immunotherapeutic efficacy. These findings identify CNPs as a promising strategy to overcome CSC-driven resistance and remodel the CRC immune microenvironment.
ABSTRACT Oxidative stress, defined as an imbalance between the production and clearance of reactive oxygen species (ROS), is not merely a reflection of metabolic or microenvironmental stress but an active signaling and regulatory hub in cancer. ROS function as key signaling molecules that drive tumorigenesis, metabolic reprogramming, and epigenetic remodeling. However, a systematic view of the spatiotemporally organized, bidirectional crosstalk between ROS and the DNA epigenetic machinery, particularly under conditions such as hypoxia, remains incomplete. This review synthesizes current understanding of this bidirectional axis. We detail how ROS reshape the DNA epigenetic landscape by modulating DNA methyltransferases and ten‐eleven translocation family protein (TET) dioxygenases, altering profiles of 5‐methylcytosine and its oxidized derivatives, and how epigenetic modifications in turn regulate ROS homeostasis through antioxidant and metabolic pathways. We further explore the cascade regulation of this interaction within the hypoxic tumor microenvironment and evaluate combined intervention strategies targeting both redox and epigenetic mechanisms. Emerging therapeutic avenues are highlighted, including spatiotemporally controlled ROS modulation, CRISPR‐based epigenome editing, ROS‐responsive proteolysis‐targeting chimeras, artificial intelligence (AI)‐driven multi‐omics prediction, and tissue‐specific delivery platforms. By integrating these insights, this review provides a framework for developing ROS‐guided precision epigenetic reprogramming strategies, offering novel therapeutic opportunities in cancer.
ABSTRACT Endometrial cancer (EC) is one of the most common gynecological malignancies worldwide. Classified as an immunologically “cold” tumor, EC exhibits a tumor immune microenvironment (TIME) that critically influences tumor initiation, progression, and therapeutic response. This review systematically examines the composition and functional characteristics of the TIME in EC, including the distribution and phenotypic states of major immune cell populations—such as tumor‐associated macrophages, myeloid‐derived suppressor cells (MDSCs), and T lymphocytes—as well as key non‐immune components, including cancer‐associated fibroblasts and cytokines. We further elucidate mechanisms of immune suppression, primarily mediated by the programmed cell death‐1/programmed death‐ligand 1 (PD‐1/PD‐L1) pathway and the consequent immune evasion processes. Integrating molecular classifications of EC, we analyze the immunogenicity of distinct TIME subtypes and their differential responses to immunotherapy. Recent advances in immune‐based therapeutic approaches are also highlighted, encompassing immune checkpoint blockades, adoptive cell therapies, cancer vaccines, and combination regimens with chemotherapy or molecularly targeted agents. Collectively, this review emphasizes the intricate complexity of TIME in EC, evaluates the strengths and limitations of current immunotherapies, and offers forward‐looking perspectives to guide future research and clinical translation, particularly in the identification of novel therapeutic targets and the advancement of precision oncology strategies.
ABSTRACT Hepatocellular carcinoma (HCC) is a prevalent and aggressive malignancy with rising incidence and mortality rates worldwide. Accumulating evidence indicates that dysregulated lipid metabolism is crucial in HCC development, progression, and treatment resistance, making it a promising target for prevention and intervention against HCC. However, a comprehensive understanding of the heterogeneity of lipid metabolism in HCC driven by distinct etiologies, its role in HCC progression and immunosuppression, and the relevant molecular mechanisms remains limited, which impedes advances in strategies targeting lipid metabolism. This review introduces the primary pathways of hepatic lipid metabolism, encompassing intake, synthesis, storage, catabolism, and excretion of lipids. It also summarizes the mechanisms underlying aberrant lipid metabolism in HCC and the molecular drivers of lipid dysregulation during hepatocarcinogenesis. Furthermore, this review delineates the hallmarks of lipid metabolic reprogramming in HCC cells, and highlights the impact of disordered lipid metabolism on malignant potential of HCC cells and the immunosuppressive tumor microenvironment. Finally, the strategies for harnessing lipid metabolism to prevent and treat HCC are emphatically discussed. By integrating these insights, this review deepens the understanding of the relationship between lipid metabolism and HCC, laying a foundation for optimizing preventive and therapeutic strategies against this malignancy.
ABSTRACT Enhancer of zeste homolog 2 (EZH2), a core histone methyltransferase in polycomb repressive complex 2 (PRC2), can regulate various downstream genes or proteins in a PRC2‐dependent or PRC2‐independent manner. Dysregulation of EZH2 is closely related to cancer progression and therapy resistance. However, targeting EZH2 for cancer therapy still encounters many challenges and needs further exploration. In this review, we elaborate on the biological functions and molecular mechanisms of EZH2 in cancer progression, drug resistance, and tumor microenvironment, highlighting its potential significant value as a tumor biomarker and therapeutic target. We also expound the cancer treatment strategies based on targeting EZH2 and outline the anti‐cancer effects and regulatory mechanisms of selective small‐molecule inhibitors, degraders and natural compounds which target EZH2 in various preclinical cancer models. In addition, we summarize the applications of EZH2 selective small‐molecule inhibitors and combination therapy in clinical trials and discuss the opportunities and challenges of targeting EZH2 for cancer treatment. We aim to highlight the significance of targeting EZH2 in cancer and explore more targeted therapeutic strategies for clinical translation and cancer therapy.
ABSTRACT Reactive oxygen species (ROS) play a profoundly central and multifaceted role in orchestrating the complex dynamics of the tumor immune microenvironment (TIME). Oxidative stress, driven by elevated ROS levels, is considered a key regulator of tumor progression, immune cell function, and immune evasion. Although the profound impact of oxidative stress on initial oncogenesis and cellular proliferation is extensively documented, its specific contribution to TIME remodeling and subsequent immune escape warrants further investigation. This review systematically summarizes the core mechanisms of ROS and oxidative stress in the TIME. We elucidate how dysregulated ROS, generated by both malignant tumor cells and infiltrating immune populations, synergistically promote continuous tumor progression, profound local immunosuppression, and pervasive therapy resistance. Specifically, we discuss in detail how sustained oxidative stress critically alters diverse immune cell functions, fundamentally reshaping the TIME landscape, and explore oxidative stress–mediated intercellular communication networks, including metabolic competition and the release of soluble factors. By strategically bridging fundamental redox biology with emerging clinical oncology applications, this review provides novel therapeutic perspectives on modulating redox homeostasis to effectively reverse immunosuppression and bolster anti‐tumor immunity.
ABSTRACT Autophagy is an evolutionarily conserved lysosomal degradation pathway that maintains cellular homeostasis by eliminating dysfunctional organelles and protein aggregates. Dysregulated autophagy contributes to pathologies including cancer, where it exhibits a dual context‐dependent role. A comprehensive synthesis integrating molecular mechanisms with stage‐specific functions and therapeutic implications of autophagy in cancer remains lacking. In this review, we provide an overview of the core molecular machinery and regulatory networks governing autophagy, integrating with fundamental principles of cancer pathogenesis. We comprehensively discuss the tumor‐suppressive functions of autophagy during cancer initiation, contrasting these with its tumor‐promoting roles in driving tumor progression and metastasis. Moreover, this review covers current strategies for the therapeutic modulation of autophagy, including both activation and inhibition, with a focus on their applications in cancer therapy through monotherapy and combination approaches. The clinical progress and challenges of autophagy‐targeted drugs such as chloroquine (CQ) and hydroxychloroquine (HCQ) are also discussed. We further discuss the potential of autophagy‐related components as biomarkers in cancer. Taken together, understanding the role of autophagy in cancer not only expands the functional scope of autophagy, but also provides a solid foundation for development of novel preventive and therapeutic strategies against cancer.
ABSTRACT Ribosomal proteins (RPs), long regarded as essential structural components of the ribosome, are now increasingly appreciated as multifunctional regulators that extend beyond their canonical roles in protein synthesis. They actively modulate key cellular processes, including transcription, DNA damage response, cell cycle progression, and stress signaling, thereby influencing both physiological homeostasis and disease states. Despite substantial advances in structural and functional characterization, the mechanistic underpinnings linking RP dysregulation to human pathogenesis remain incompletely defined, constituting a significant gap in our understanding. This review synthesizes recent evidence illuminating the dual nature of RPs in health and disease, with a particular emphasis on cancer. Under conditions of ribosomal stress, RPs activate tumor‐suppressive pathways, whereas their dysregulation can promote oncogenesis. Beyond cancer, RPs' defects contribute to ribosomopathies, neurodegenerative disorders, and inflammation, highlighting their broad pathophysiological relevance. We also evaluate the translational potential of RPs as diagnostic and prognostic biomarkers, and review emerging therapeutic strategies targeting ribosomal pathways. Finally, we discuss current challenges, such as context‐dependent RP functions, ribosome heterogeneity, and therapeutic specificity. By integrating mechanistic insights with translational prospects, this review positions RPs as pivotal nodes bridging fundamental biology and clinical application, offering a conceptual framework to guide precision medicine efforts in RP‐associated diseases.
ABSTRACT Brain cancer, particularly malignant gliomas, poses a formidable clinical challenge due to its high mortality, intratumoral heterogeneity, and resistance to conventional therapies, accounting for substantial global cancer fatalities. Despite decades of research, therapeutic progress remains modest, largely hindered by the blood–brain barrier (BBB) and blood–tumor barrier (BTB), which impede drug delivery and contribute to dismal prognoses. This review addresses the critical gap in integrating diagnostic and therapeutic strategies within a unified theranostic framework for brain cancer management. It systematically examines BBB structural/functional complexities and drug delivery implications, alongside advanced magnetic‐resonance imaging (MRI)/positron‐emission tomography (PET) for tumor characterization, treatment planning, and response assessment. Emphasis is placed on BBB‐crossing strategies, including receptor‐mediated transcytosis (RMT), adsorptive‐mediated transcytosis (AMT), focused ultrasound (FUS), convection‐enhanced delivery (CED), and intra‐arterial administration, highlighting mechanistic principles and translational potential. Nanoparticles (NPs)‐based systems (polymeric, lipidic, and metallic) are discussed for enhancing bioavailability, overcoming efflux resistance, and enabling multimodal therapies like photodynamic therapy (PDT) and immunotherapy. This review highlights the translational potential of nanotechnology, immuno‐oncology, and computational methods in closed‐loop theranostic models for real‐time monitoring, adaptive therapy, and improved brain cancer survival and quality of life, offering insights to advance clinical outcomes.
ABSTRACT Colorectal cancer (CRC) is one of the most common and lethal cancers globally, with early detection of precancerous lesions being crucial for reducing its incidence and mortality. Colorectal precancerous lesions, including adenomas, serrated lesions, and dysplasias associated with inflammatory bowel disease (IBD), represent key targets for preventive strategies. Despite advancements in screening and therapeutic options, medicinal natural products clinical application is frequently challenged by low bioavailability, complex in vivo metabolism, unclear adverse effects and side‐effect profiles, and a strong reliance on empirical standards in clinical use. This review provides a comprehensive overview of the definition, classification, and molecular mechanisms underlying colorectal precancerous lesions, epigenetic modifications, and genetic factors. It also highlights the application of multi‐omics technologies in understanding lesion heterogeneity. In addition, the review evaluates cutting‐edge research models such as organoids, 3D co‐culture systems, and various in vivo models, offering insights into their potential for studying CRC precursors. This review summarizes current mechanistic insights into early colorectal carcinogenesis and highlights three major translational directions: therapeutic strategies targeting key genomic alterations; immunologic modulation relevant to inflammation‐driven tumor initiation; and multi‐omics stratification optimizing dosing and patient selection. These perspectives outline emerging opportunities for developing more precise and clinically actionable preventive interventions.
ABSTRACT The parallels between embryonic development and tumorigenesis have reshaped how we conceptualize cancer's molecular foundations. Once viewed as purely mutation‐driven, malignancy is now understood to involve the systematic reactivation of embryonic gene programs—raising a fundamental question: How extensively do tumors co‐opt developmental machinery to sustain their aggressive phenotypes? This review provides a comprehensive synthesis integrating developmental biology, reproductive medicine, and molecular oncology. It systematically examines how tumor cells exploit core developmental machinery, including pluripotency maintenance networks, evolutionarily conserved signaling pathways and epigenetic reprogramming mechanisms, such as DNA methylation, histone modifications, and non‐coding RNA regulation, to acquire stemness properties, drive epithelial‐mesenchymal transition (EMT), remodel the extracellular matrix (ECM), and establish immunosuppressive microenvironments. We further explore germ cell tumor biology, assisted reproductive technology (ART) implications, and DNA damage response vulnerabilities from a developmental perspective. These molecular insights furnish tangible opportunities: biomarker discovery rooted in fetal antigen re‐expression, and therapeutic strategies that selectively disrupt the “embryonic” state of cancer cells while sparing normal tissue. This review synthesizes the core molecular mechanisms connecting embryonic development and tumorigenesis from a multidisciplinary standpoint and outlines future research trajectories and clinical applications, thereby contributing new insights and actionable strategies in the fight against cancer.
