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.

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.

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.

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.

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.

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.

Despite the pivotal role of tumor immune microenvironment (TIME) in breast cancer (BC) progression, the functional contributions of mast cells (MCs) within the TIME remain poorly understood. Utilizing single-cell RNA sequencing on tumor (T) and adjacent para-tumor (PT) tissues from BC patients, we identified a distinct transcriptional profile in T-derived tumor-resident MCs (MCt) compared to their PT counterparts. Survival analysis revealed that MCt signature gene set significantly correlated with poor clinical outcomes. To assess functional roles, we established in vitro co-culture systems and in vivo murine allograft models, which demonstrated that MCt promoted BC cell proliferation and enriched ALDH⁺ breast cancer stem cells (BCSCs). Mechanistically, through molecular inhibitors, agonist, recombinant protein, and gene-knockdown cell lines, we found that MCt-derived IFNB1 activated the Type I interferon pathway in BC cells via the IFNAR1-STAT1 axis. Reciprocally, BC cells upregulated IFNB1 expression in MCs via stem cell factor (SCF)-mediated c-KIT-MAPK/ERK signaling. This bidirectional crosstalk established a self-reinforcing IFNB1/SCF feedforward loop driving BC progression and stemness, which was further validated in BC patient tissues by multiplex immunohistochemistry. Collectively, our findings characterize a pro-tumorigenic MC subset within the TIME and propose a potential novel therapeutic strategy for BC by disrupting the MCt-BC cell interplay.

Chromatin abnormalities are a hallmark of cancer, but the role of the chromatin remodeler CHD4 in multiple myeloma (MM) remains unclear. This study aims to elucidate how CHD4 drives MM progression and to explore targeted therapeutic strategies. Using CHD4 overexpression and knockdown models in MM cell lines, we found that elevated CHD4 correlates with poor prognosis and increased proliferation. Mechanistically, we performed chromatin profiling and luciferase reporter assays to show that the ATPase domain of CHD4 resolves G-quadruplex structures in the c-Myc promoter, thereby enhancing chromatin accessibility. Co-immunoprecipitation (Co-IP) and chromatin immunoprecipitation (ChIP) further revealed that CHD4 stabilizes c-Myc activity through liquid-liquid phase separation (LLPS), increasing c-Myc chromatin retention and promoter occupancy. To identify CHD4 targets, we integrated RNA-seq with chromatin profiling. Structure-based drug design identified luteolin 7-O-glucuronide (LUT) as an inhibitor of CHD4's ATPase domain and idarubicin (IDA) as an inhibitor of its chromatin-interaction domain; combination treatment synergistically suppressed MM proliferation in adoptive B-cell transfer, xenograft, and 5TMM3VT mouse models. Our findings establish CHD4 as a key oncogenic driver in MM and propose a LUT/IDA combination as a precision medicine strategy, advancing the understanding of chromatin remodeling in cancer.

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.

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.