For decades, cellular senescence has been treated as a terminal cell fate defined by durable proliferative arrest and a pro-inflammatory secretory program. Quiescence, by contrast, has been viewed as a reversible, metabolically restrained state that enables tissue homeostasis and stem cell maintenance. Rather than treating these as categorically distinct fates, recent work across aging, stem cell, and cancer biology suggests that arrested cells continuously evaluate whether to maintain a reversible state, progress toward stable senescent arrest, or re-enter proliferation. These outcomes are governed not by categorical state identity alone, but also by switch-like regulatory behavior within stress-response networks integrating cellular stress, metabolic capacity, and quality-control machinery. This perspective reframes quiescence and senescence not as categorically distinct endpoints, but as positions along a continuum of arrested states defined by their stability and by the magnitude of the perturbation required to reverse them. Importantly, this reframing does not diminish the biological complexity of senescence. Features that distinguish senescent cells from quiescent cells, including the senescence-associated secretory phenotype (SASP), metabolic reprogramming, and chromatin remodeling, are retained as active, context-dependent components of the senescent program. Within this framework, senescence is viewed not as a unique or exceptional state, but as one outcome within a broader landscape of cell-cycle exit decisions. Consequently, cellular fate is better understood as a dynamic balance between damage accumulation and the capacity of quality-control systems to preserve reactivation competence. We propose a Maintenance Threshold Model (MTM) in which arrest-state stability emerges from the balance between maintenance capacity and accumulated cellular stress. Rather than pooling these inputs, the model proposes that they are gated in series, such that proteostatic and organellar maintenance capacity determines whether an arrested cell can complete division independently of whether the Rb-E2F restriction point is traversed. It further proposes that senescent-cell persistence is set by two independent, aging-sensitive thresholds: cell-autonomous maintenance capacity and non-cell-autonomous immune surveillance. We introduce a therapeutic framework comprising three strategies; state-locking, metabolic inflexibility targeting, and program hijacking, that exploit fate plasticity for cancer treatment and aging interventions. This review develops a decision-centric framework in which quiescence, senescence, and proliferation emerge as dynamically stabilized states shaped by tunable regulatory thresholds rather than fixed endpoints.
The therapeutic efficacy of immune checkpoint blockade is frequently compromised by the profound spatial heterogeneity of solid tumors, where distinct ecological niches are associated with different patterns of immune engagement. Spatial omics has substantially refined our understanding of tumor immune topographies. These range from immune-excluded hypoxic and necrotic cores to immune-infiltrated margins enriched with tertiary lymphoid structures (TLS). However, the mechanistic contribution of regulated cell death (RCD) to these spatial domains remains largely unexplored. In this review, we propose the concept of spatially organized RCD-immune coupling as a hypothesis-generating framework. We argue that RCD modalities are not uniformly distributed across tumors, but are influenced by regional microenvironmental constraints, including metabolic zonation, hypoxia, and mechanical stress. Synthesizing emerging evidence, we discuss how apoptosis, necroptosis, pyroptosis, ferroptosis, and PANoptosis may be enriched within distinct tumor niches. We further examine how region-specific release of damage-associated molecular patterns (DAMPs), cytokines, and lipid mediators may be associated with local immune activation, exhaustion, or exclusion. Importantly, we distinguish spatial association from functional causality and emphasize the need for phenotypic validation and perturbation-based studies. This framework positions RCD as a spatially organized component of tumor immune ecology and a basis for future biomarker and therapeutic studies.
Over the past decade, the number of microbial communities identified within tumors has increased by 400
Proficient mismatch repair/microsatellite-stable colorectal cancer (pMMR/MSS CRC), which represents the majority of clinical cases, exhibits low tumor mutational burden and minimal responsiveness to immune checkpoint blockade. Disrupting the MMR system has been shown to resensitize pMMR/MSS CRC to immune surveillance; however, direct MMR inhibitors are currently unavailable. Here, we bridge this gap by developing small interfering RNA lipid nanoparticles (siMMR@LNPs) capable of silencing key MMR genes, including MLH1, MSH2, and MSH6, achieving over 70
Cancer progression is an evolutionary process shaped by clonal dynamics within a complex tumor ecosystem. Deciphering tumor evolution solely as the gradual accumulation of mutations that confer selective advantages and promote the expansion of selected cellular clones does not fully capture the complexity and dynamics of cancer development. Emerging evidence increasingly underscores the critical contribution of non-genetic regulatory mechanisms in shaping cellular behavior, revealing a remarkable degree of cellular plasticity that enables cells to dynamically adapt their phenotype and functional state in response to intrinsic and extrinsic cues. In this review, we discuss how tumor evolution is propelled not only by stable genetic mutations, which initiate malignant transformation and confer proliferative advantages, but also by dynamic adaptive programs. These mechanisms, including the epithelial–mesenchymal transition, cellular dormancy and metabolic reprogramming, enable tumor cells to survive microenvironmental stress and facilitate metastatic dissemination. Herein, we conceptualize tumor progression as the evolutionary selection of highly adaptable clonal populations, governed by a synergistic interplay between genetic fitness and cellular plasticity. We propose that understanding the convergence of stable genetic alterations and reversible epigenetic states is critical for developing novel therapeutic strategies to effectively target metastatic disease.
The tumor microenvironment (TME) exhibits widespread immunophenotypic heterogeneity. Based on the spatial immune contexture, tumor immune profiles can be classified as immune-inflamed, excluded, or desert. Immune-excluded tumors, a distinct tumor immune phenotype, are characterized by the presence of immune cells (especially CD8+ T cells) near tumors but a lack of direct physical contact between immune and tumor cells. Accumulating evidence indicates that tumor immune exclusion is a spatially organized and actively maintained microenvironmental state associated with poor prognosis, impaired T cell infiltration, and resistance to immunotherapy. However, the biological mechanisms and spatial profiling underlying this phenotype remain unclear. Advances in spatial omics technologies and analytical tools have enabled the dissection of the complex spatial architecture of immune-excluded tumors. In this review, we describe recent insights into the core cellular subsets and spatial interaction networks of immune-excluded tumors, incorporating the spatial immune contexture, to provide new theoretical foundations and intervention strategies targeting spatial ecotypes to enhance T cell infiltration and sensitize immune-excluded tumors to immunotherapy. Collectively, these findings support a shift from cell-centric models towards ecotype-centered frameworks in which spatially coordinated cellular alliances govern immune accessibility and therapeutic response. Furthermore, we discuss current challenges in this field, including standardization of spatial multi-omics data integration, real-time monitoring of dynamic spatiotemporal evolution, and optimization of clinical translation pathways. Future investigations should incorporate long-term sampling, organoid models, and basket trial designs to enable precise immune-intervention strategies based on spatial ecotypes.
Colorectal cancer liver metastasis (CRLM) is the primary cause of CRC-related mortality, with inevitable chemoresistance to targeted therapies and immunotherapy. N6-methyladenosine (m6A), as a crucial epigenetic regulator of gene expression and cellular physiology, involved in the pathogenesis of CRLM. Precise manipulation of m6A modifications could offer a non-pharmacological precision treatment for many diseases. However, the precise editing of m6A modification in regulating CRLM progression remains elusive. Here we integrated multi-omics and identified zinc finger and BTB domain-containing 7A (ZBTB7A) as an m6A-modified transcription factor that promoted CRLM. Mechanistically, METTL3-mediated m6A modification of ZBTB7A facilitated recognition by the m6A reader YTHDF1/3 complex, enhancing its translation and expression. This m6A-dependent regulation promoted CRLM progression via activation of the ARHGAP26/Rho GTPase signaling axis. Notably, we applied a targeted RNA m6A erasure (TRME) system to achieve site-specific demethylation at a single site (m6A_site_411666) within ZBTB7A mRNA, without perturbing m6A abundance. Temporal demethylation at this site is sufficient to inhibit the CRC cell migration. This study unveils the critical role of the METTL3/ZBTB7A/ARHGAP26 axis in the process of m6A-mediated CRLM and positions m6A precise editing as a promising therapy in the preclinical treatment of CRLM.
In the past decades, cancer-associated fibroblasts (CAFs) have emerged as central regulators of the tumor microenvironment (TME). CAFs have been implicated in extracellular matrix (ECM) remodeling, cytokine secretion and the establishment of the desmoplastic niche that supports tumor progression. Consequently, for long time, therapeutic strategies have focused on CAF depletion. However, accumulating evidence have demonstrated that indiscriminate targeting of CAFs can accelerate tumor progression, revealing their functional heterogeneity and a previously underappreciated tumor-restraining role. In this review, we examine the evolving paradigm of CAF biology, highlighting emerging tumor-suppressive CAF subtypes and their underlying mechanisms. We discuss how these findings challenge conventional therapeutic strategies and propose, based on this improved CAF stratification, a conceptual shift toward CAF exploitation rather than elimination. Ultimately, harnessing CAF anti-tumoral properties may open new avenues for more effective and context-specific cancer therapies.
Chromatin remodeling comprises a set of molecular mechanisms that regulate gene transcription, DNA replication, and DNA repair by altering nucleosome structure. Previous studies have found that chromatin remodelers are heavily mutated in cancer patients, and targeting aberrant chromatin remodeling activities holds great potential for clinical benefit. Despite these promising findings, several significant hurdles remain before this strategy can be successfully transitioned from bench to bedside. The classic concept of chromatin remodeling focuses on the linear 2D chromatin structural level. While the emergence of sophisticated sequencing modalities has underscored the significance of 3D chromatin architecture, the mechanistic underpinnings and broader implications for cancer biology continue to be largely elusive. This review provides a comprehensive synthesis of the mechanisms and functional roles of classical chromatin remodelers within both physiological and neoplastic contexts. Furthermore, we integrate emerging insights regarding the cohesin complex as a primary mediator of three-dimensional (3D) genomic organization. By proposing a hierarchical framework that distinguishes between 'first-level' (classical) and 'higher-order' chromatin remodeling, we aim to provide a more holistic understanding of the integrated regulatory networks governing chromatin architecture. Furthermore, we have systematically cataloged the landscape of therapeutic strategies targeting chromatin remodelers in oncology. By evaluating the divergence between clinically approved therapies and those currently in developmental pipelines, we delineate the primary challenges confronting the field and propose strategic directions for future research. Collectively, we have delineated the multifaceted contributions of chromatin remodeling to cancer progression. The strategic modulation of these remodeling processes represents a vital frontier in the development of novel therapeutic interventions and is likely to emerge as a primary focus for future cancer management strategies.
Resistance to therapy remains a critical challenge in cancer. This is exemplified by TGF-β pathway inhibitors which, despite broad clinical testing, have failed to deliver survival benefit. More precise SMAD3 targeting has shown preclinical promise, yet resistance mechanisms to SMAD3 inhibition remain entirely unknown. Using complementary genome-wide CRISPR activation and knockout screens, we discover that cancer cells escape SMAD3 inhibition through metabolic reprogramming. Strikingly, this escape is driven not by transcriptional bypass but by the lactate transporter MCT1, with the effect preserved across BRAF-mutated melanoma, KRAS-mutated lung adenocarcinoma, and mouse melanoma. Mechanistically, SMAD3 inhibition creates energetic stress that cancer cells exploit through MCT1. By conferring metabolic flexibility and switching toward glycolysis under drug pressure, MCT1 increases anabolic activity to drive lipid and cholesterol synthesis. Pharmacological and genetic MCT1 inhibition synergizes strongly with SMAD3 blockade to impair tumor viability in BRAF-mutated melanoma, while suppressing drug-tolerant cell emergence in BRAF inhibitor-resistant cells. Critically, this synergy extends to preclinical models, where co-inhibition of SMAD3 and MCT1 potently reduces tumor growth in vivo. Given the additional and well-established role of MCT1 in shaping the tumor immune microenvironment via lactate transport, these results position MCT1 as both a metabolic and immunological target and provide a strong rationale for the repurposing of TGF-β/SMAD3 pathway inhibitors in combination.
T cell exhaustion has traditionally been defined as a state of progressive functional impairment and specific epigenetic remodeling induced by chronic antigen stimulation. However, emerging multidisciplinary evidence indicates that exhaustion is not merely a terminal stage of functional failure; rather, it represents an evolutionarily conserved adaptive program designed to balance long-term immune surveillance with the limitation of excessive pathological damage. This review focuses on the positive regulatory roles of T cell exhaustion within the tumor microenvironment. It elucidates how the exhausted state avoids lethal inflammation by restraining excessive activation while preserving a durable progenitor pool, thereby ultimately establishing a homeostatic balance between sustained tumor control and host survival. Overall, a comprehensive understanding of the evolutionary principles underlying this adaptive program provides important guidance for the design of precision immunotherapies that balance efficacy and safety. Strategically targeting and harnessing these protective features may greatly optimize the clinical benefits of solid tumor treatment and guide the development of next-generation innovative immunotherapies.
Protein ubiquitination is among the most important posttranslational modifications in eukaryotes. It precisely regulates protein stability and cellular signaling through the ubiquitin‒proteasome system (UPS). A dynamic equilibrium network formed by the E1-E2-E3 enzymatic cascade and deubiquitinating enzymes (DUBs) plays a central role in cell cycle regulation, DNA damage repair, and signal transduction. In tumorigenesis and cancer progression, the UPS regulates key factors such as p53 and p27 to control cell proliferation and apoptosis. It is involved in the activation of oncogenic pathways, including the PI3K/Akt, Wnt/β-catenin, and NF-κB pathways, and regulates cancer stem cell maintenance and tumor immune microenvironment remodeling. On the basis of these mechanisms, significant progress has been made in therapeutic strategies targeting the UPS. Proteasome inhibitors have become standard treatments for multiple myeloma. Proteolysis-targeting chimera (PROTAC) technology overcomes the limitations of “undruggable” targets and enables the specific degradation of pathogenic proteins such as the androgen receptor (AR) and estrogen receptor (ER). Molecular glue degraders exert antitumor effects by reshaping the substrate recognition interface of E3 ligases. E3 ligase inhibitors and DUB inhibitors are also entering clinical development. However, the selective toxicity, pharmacokinetic limitations of PROTACs, and acquired resistance remain major challenges. Future research should focus on optimizing drug design and delivery strategies to reduce systemic toxicity and establish a ubiquitination biomarker-guided precision medicine framework. ∙ Ubiquitination is a reversible posttranslational modification regulated by the E1-E2-E3 enzymatic cascade and deubiquitinases (DUBs). Distinct ubiquitin chain linkages (e.g., K48-, K63-, and M1-linked chains) determine the fate of substrate proteins. ∙ The ubiquitin system regulates core cell cycle regulators, including cyclins, cyclin-dependent kinase inhibitors (CKIs), and the tumor suppressor p53, thereby controlling cell cycle progression or arrest. ∙ Major protumorigenic signaling pathways, including the PI3K/Akt, Wnt/β-catenin, and NF-κB pathways, are extensively regulated by ubiquitination. ∙ Ubiquitination contributes to the maintenance of cancer stem cell (CSC) stemness. ∙ In the tumor microenvironment (TME), ubiquitination regulates immune evasion, immune cell function, and stromal cell reprogramming. ∙ Strategies targeting the ubiquitin system, such as proteasome inhibitors, E3 ligases and DUB modulators, and targeted protein degradation technologies, such as proteolysis-targeting chimeras (PROTACs) and molecular glue degraders (MGDs), have emerged as rapidly advancing therapeutic strategies in cancer. ∙ Therapies targeting the ubiquitin‒proteasome system (UPS) are limited by selective toxicity, the limited druggability of PROTACs, and acquired resistance.
Hypoxia, a hallmark of solid tumours, profoundly alters cellular metabolism to enable survival in the harsh tumour microenvironment. Whilst effects on carbohydrate and protein metabolism are well characterised, the hypoxic regulation of lipid metabolism remains poorly understood. Recent advances in lipidomics have revealed that lipids not only serve as energy resources, but have critical roles in oncogenic signalling, cell homeostasis and membrane metabolism. Understanding hypoxia-driven lipid reprogramming could uncover new therapeutic opportunities. A scoping review was conducted following internationally accepted guidelines and reported using the PRISMA-ScR Checklist. MEDLINE, Embase, and Web of Science were searched from inception to 31st August 2025 using tailored strategies, supplemented with grey literature and reference snowballing. Eligible studies included original peer-reviewed research investigating hypoxia and lipid metabolism in cancer using in vitro, in vivo, or human models with physiologically relevant hypoxic conditions. Data were extracted and thematically analysed across four domains: lipid accumulation, lipolysis, membrane metabolism, and lipid signalling. From 4632 records identified, 53 studies met the inclusion criteria. Most investigations used immortalised 2D cancer cell lines exposed to chronic, moderate hypoxia (1–2
The serotonin axis, encompassing the biosynthesis, transport, receptor signaling and metabolism of serotonin, has emerged as a context-dependent regulatory network implicated in cancer biology. Beyond its classical neurotransmitter functions, serotonin modulates tumor progression through receptor-dependent signaling pathways and non-canonical mechanisms such as histone serotonylation, which directly links cellular metabolism to epigenetic regulation. Available evidence suggests that these processes can influence tumor cell proliferation, metabolic adaptation, plasticity and therapeutic drug resistance. Furthermore, the serotonin axis plays a context-dependent role in shaping the tumor microenvironment by regulating the functions of T cells, macrophages and other stromal components, thereby influencing responses to cancer immunotherapy. These diverse regulatory mechanisms have prompted the development of therapeutic strategies targeting serotonin biosynthesis and metabolism, serotonin transport, receptor signaling, and serotonylation, although their efficacy remains highly context-dependent. We further discuss emerging mechanistic insights, unresolved questions, and the opportunities and challenges for developing context-dependent therapeutic strategies targeting this axis.
Triple negative breast cancer (TNBC) represents the most malignant subtype of breast cancer, with heightened invasiveness, frequent recurrence and poor prognosis. Deciphering the molecular mechanisms underlying TNBC pathogenesis and drug resistance is critical for developing precision therapeutics. Through deep-coverage phosphoproteomic profiling of trace clinical specimens across breast cancer subtypes, we identified phosphorylation at serine 39 (S39) on aldolase A (ALDOA) as a TNBC-specific event. Tissue microarray (TMA) analysis, functional assays, ubiquitination and proteasomal degradation assays, glucose metabolism measurements, TurboID IP–MS, and co-immunoprecipitation (Co-IP) were used to define the functional role of ALDOA S39 phosphorylation and its regulatory interactions with TRIM25 and MINK1. To establish translational relevance, we employed multiple preclinical models, including cell line-derived xenografts, patient-derived organoids, and patient-derived orthotopic xenografts to evaluate therapeutic targeting of the MINK1–ALDOA axis. Phosphorylation of ALDOA at serine 39 was identified as a TNBC‑associated phosphorylation event. This phosphorylation attenuated TRIM25-mediated ubiquitination, thereby impairing proteasomal degradation and stabilizing ALDOA protein. Stabilized ALDOA enhanced glycolysis, as indicated by increased glucose uptake, lactate secretion, and ATP production, ultimately driving TNBC progression. We further identified MINK1 as the upstream kinase responsible for ALDOA-S39 phosphorylation. Pharmacological inhibition of MINK1 with the selective small-molecule inhibitor KY-05009 effectively destabilized ALDOA, suppressed glycolysis, and attenuated tumor growth and metastasis across multiple preclinical models. Our findings reveal the MINK1–ALDOA axis as a central regulator of glucose metabolic reprogramming and nominate this pathway as a promising therapeutic target for metabolic intervention in TNBC.
Initially characterized as an epigenetic marker for transcriptional regulation, lysine lactylation is now recognized as a pervasive posttranslational modification with extensive functions beyond those associated with chromatin. Recent methodological advances in the resolution of stereoisomeric dynamics have established L-lactylation as the predominant glycolysis-derived functional form, providing a metabolic switch that couples glycolytic flux to oncogenic signaling. Here, we provide a comprehensive overview of non-histone L-lactylation in cancer biology. We define the spatially compartmentalized catalytic network governing this process, detailing how nuclear EP300/CBP, cytosolic AARS1, and mitochondrial AARS2 mediate stereospecific targeted modifications. At the molecular level, non-histone L-lactylation alters protein biophysics via charge neutralization, steric hindrance, and interface remodeling. These physicochemical alterations govern fundamental enzymatic kinetics, complex assembly, subcellular trafficking, and proteasomal degradation processes. Through primarily transcription-independent mechanisms, L-lactylation enables cancer cells to sustain metabolic flexibility, promote the repair of damaged DNA, and foster an immunosuppressive tumor microenvironment. Because tumors exploit these regulatory networks to drive adaptive resistance across diverse therapeutic modalities, we examine current strategies for pharmacological intervention. Finally, we highlight critical unresolved questions in this field. Notably, the identification of lactylation-specific readers and the development of stereoisomer-resolved chemobiological tools will be essential to fully leverage this metabolism–modification axis for cancer therapy.
Alternative polyadenylation (APA) is a pervasive post-transcriptional regulatory mechanism that generates transcript isoforms with distinct 3′ untranslated regions, terminal exons, or coding potential, thereby influencing mRNA stability, translation, localization, and protein output. Rather than representing a uniform 3′UTR-shortening process, APA comprises heterogeneous 3′-end regulatory events, including tandem 3′UTR APA and upstream APA events such as intronic polyadenylation (IPA), which differ in mechanisms, detection strategies, functional consequences, and clinical interpretation. Dysregulated APA is increasingly recognized as an important contributor to cancer initiation and progression. Tandem 3′UTR APA can remove miRNA- or RNA-binding protein-mediated repression and enhance oncogenic transcript output, whereas upstream APA events, including IPA, can generate prematurely terminated RNAs, truncated proteins, soluble isoforms, or neoantigenic products. In this review, we summarize the classification and biological consequences of major APA events, as well as experimental and computational approaches for APA analysis. We then discuss regulatory mechanisms involving core 3′-end processing factors, RNA-binding proteins, splicing–polyadenylation coupling in upstream APA/IPA, transcription-associated regulation, and promoter–terminator communication. Functionally, aberrant APA contributes to proliferation, invasion and metastasis, metabolic reprogramming, tumor microenvironment remodeling, antitumor immunity, and immune escape. Finally, we highlight APA events, APA regulators, 3′UTR-based signatures, and upstream APA/IPA-derived products as emerging biomarkers and discuss small-molecule, RNA-based, and CRISPR-based strategies for targeting APA or 3′-end processing in cancer.
Tumors are embedded within complex microenvironments composed of malignant, immune and stromal cells, yet how coordinated cellular organization shapes tumor biology across cancers remains incompletely understood. Here we integrate single-cell transcriptomic profiles from over two million cells spanning 19 human epithelial cancers to construct a comprehensive pan-cancer atlas of tumor microenvironment (TME) organization. We identify cell subsets selectively enriched in tumors compared with normal tissues and show that their relative abundance is associated with clinical outcomes. By clustering tumors according to their cellular composition, we define eight recurrent cellular ecosystem subtypes that capture coordinated variation in immune and stromal architectures across cancer types. Comparative analyses reveal that these ecosystem states are associated with distinct tumor-intrinsic molecular programs, including differences in signaling pathway activity, transcriptional regulation and copy number alterations. We further uncover subtype-specific patterns of ligand–receptor interactions linking malignant cells with immune and stromal compartments and provide independent spatial support for these interactions using spatial transcriptomic data. Together, this work provides a unified framework for tumor ecosystem stratification and highlights cellular organization as a key dimension of tumor heterogeneity with potential implications for precision cancer therapy.
