搜索结果：Biochimica et biophysica acta. Reviews on cancer

Cancer remains the second leading cause of death worldwide, surpassed only by cardiovascular diseases. Although cancer-specific mortality rates have declined due to advances in early detection and therapeutic strategies, the absolute number of cancer-related deaths continues to rise, driven by increasing disease incidence associated with population aging and lifestyle factors. A substantial proportion of cancer mortality is attributable to the development of resistance to anticancer therapies, making drug resistance a critical barrier to durable treatment efficacy and a major focus for clinical and translational research. Drug resistance arises from a wide spectrum of molecular and microenvironmental adaptations that enable cancer cells to limit drug uptake, neutralize or bypass drug activity, and evade therapy-induced cell death. These adaptive processes are orchestrated by extensive rewiring of gene expression programs, regulatory networks, and signaling pathways, ultimately reshaping cellular metabolism and stress responses. Traditionally, such adaptations have been primarily ascribed to genetic alterations and transcriptional reprogramming. However, growing evidence indicates that posttranscriptional regulatory mechanisms play a pivotal and previously underappreciated role in modulating gene expression and protein activity during the acquisition of drug-resistant phenotypes. RNA-mediated mechanisms, including regulation of mRNA stability, translation, subcellular localization, and RNA-protein interactions, introduce a dynamic and reversible level of control over protein expression and activity. In particular, non-canonical RNA-binding proteins, diverse classes of non-coding RNAs, and riboregulatory mechanisms have emerged as critical modulators of pathways involved in drug transport, DNA damage response, apoptosis, and metabolic adaptation. These processes allow cancer cells to rapidly fine-tune functional proteomes without requiring permanent genetic changes, thereby facilitating phenotypic plasticity and therapeutic escape. In this review, we summarize recent advances in the field, with a particular emphasis on emerging posttranscriptional mechanisms of gene regulation that contribute to anticancer drug resistance. By highlighting the dynamic and multilayered nature of RNA-mediated regulatory processes, we aim to provide a comprehensive framework for understanding how cancer cells adapt to therapeutic pressure and to identify novel avenues for therapeutic intervention in the context of drug-resistant disease.

MYC family transcription factors are central regulators of cell growth, proliferation, metabolism, differentiation, and apoptosis, and their dysregulation contributes to many human cancers. c-Myc, N-Myc, and L-Myc share a conserved basic helix-loop-helix leucine zipper domain that mediates MAX dimerization and DNA binding, yet they differ in tissue distribution, developmental roles, modes of activation, and tumor-type associations. In this review, we synthesize current knowledge of the MYC oncogenic network, with emphasis on upstream activation mechanisms, post-translational regulation, transcriptional outputs, structural features relevant to drug discovery, and emerging therapeutic strategies. We discuss how c-Myc and N-Myc integrate oncogenic signaling with chromatin regulation, lineage plasticity, metabolic rewiring, immune modulation, and therapy resistance in a context-dependent manner. We also summarize the therapeutic landscape, including direct disruption of MYC-MAX interactions, stabilization of MAX homodimers, interference with DNA binding, inhibition of transcriptional and epigenetic dependencies, modulation of MYC protein stability, targeted degradation approaches, metabolic interventions, and emerging strategies against extrachromosomal DNA-driven MYC amplification. Recent clinical progress with Omomyc-derived OMO-103 and other MYC-network-targeting agents supports the feasibility of therapeutically intercepting this historically challenging pathway. However, because many MYC-directed strategies affect essential transcriptional, chromatin, and metabolic programs, future development will require careful biomarker selection, rational combinations, and rigorous evaluation of therapeutic windows. By integrating mechanistic and translational literature, this review highlights MYC as a dynamic cancer dependency and discusses opportunities for precision intervention.

Head and neck cancer (HNC) is a molecularly heterogeneous group of multisite malignancies that arise through two major carcinogenic routes- first, chemical carcinogenesis associated with tobacco use and/or alcohol intake, and second, infection with oncogenic human papillomaviruses (HPVs) in a clinically distinct subset of HNCs. Unlike cervical cancer, where HPV infection is typically associated with aggressive invasive disease and poor prognosis, HPV-positive HNCs generally present a more favourable clinical outcome, particularly among non-tobacco users. Conversely, HPV-negative HNC patients who are predominantly tobacco and/or alcohol users, exhibit a poor prognosis and lower survival rate. Despite significant advances in treatment strategies for HNCs, therapy resistance leading to aggressive tumor recurrence and mortality remains to be a major clinical challenge. Transcription factors (TFs), as key regulators of gene expression and cellular signalling networks, play a critical role in head and neck carcinogenesis and represent promising targets for cancer therapy. A comprehensive understanding of the transcriptional and post-transcriptional/translational regulation of TFs, as well as the molecular mechanism(s) underlying their dual role as oncogenes or tumor suppressors, is essential for the development of effective therapies. This review focuses on major transcriptional regulators transcriptional regulators with establishd or emerging relevance in HNC pathobiology including AP-1, NF-κB, STAT3 MYC, SOX2, YY1, p53, p63 and NOTCH1. We discuss their oncogenic, tumor suppressive and context-dependent functions, with emphasis on how these factors coordinate downstream signalling networks during HNC development and progression, and therapeutic resistance. Overall, dysregulation of transcription factor in HNC is not limited to single pathway activation. Instead, TFs interact with non-coding RNAs and epigenetic mechanisms to form interconnected regulatory networks that promote both tumor plasticity and create potential therapeutic opportunities. Effective targeting of these networks will require biomarker-guided and rational combination strategies tailored to tumor type.

Metabolic reprogramming is a hallmark of cancer, characterized by significant alterations in amino acid metabolism to support rapid proliferation and survival. Post-translational modifications (PTMs) have become key regulatory centers that convert oncogenic signals into metabolic changes. This review systematically examines the interplay between canonical PTMs, including phosphorylation, ubiquitination, acetylation, and methylation, and recently recognized metabolite-sensitive PTMs, including O-GlcNAcylation, lactylation, succinylation, crotonylation, and β-hydroxybutyrylation, in regulating key enzymes and transporters involved in amino acid metabolism. We describe how oncogenic pathways such as PI3K/AKT/mTOR and MYC induce metabolic changes through PTMs, and how amino acid-derived metabolites, in turn, feedback to influence signaling through "metabolite/PTM/signal" loops. Additionally, we emphasize how the PTM-amino acid metabolism axis influences the tumor microenvironment, particularly regarding immune suppression and the remodeling of the extracellular matrix. Finally, we review current clinical and preclinical therapeutic strategies that target PTM-modifying enzymes and PTM-dependent metabolic pathways. Although there are technical and biological challenges, focusing on this axis offers a promising avenue for developing personalized cancer treatments.

Brain metastases (BM) from non-small cell lung cancer (NSCLC) significantly contribute to poor prognosis, with their progression intrinsically linked to the unique immune microenvironment of the brain. This review comprehensively examines the dual regulatory roles and underlying mechanisms of three pivotal cell types within the metastatic niche-tumor-associated macrophages (TAMs), microglia, and astrocytes-during brain metastasis development. TAMs promote tumor invasion and the establishment of an immunosuppressive milieu through metabolic regulation and differentiation into functional subtypes, with profiles distinct from those in primary tumors. As resident immune cells of the central nervous system, microglia show marked functional polarization: they can inhibit metastasis by directly targeting tumor cells, cooperating with adaptive immunity, and enhancing radiosensitivity. However, under specific microenvironmental cues, they may also support tumor growth and immune evasion. Similarly, astrocytes transition from a neuroprotective to a tumor-promoting phenotype, driving progression through inflammatory cytokine secretion, gap junction-mediated intercellular communication, metabolic reprogramming, and exosomal signaling. Building on these mechanistic insights, this review further summarizes emerging therapeutic strategies targeting these cell types, including engineered vesicle-mediated TAM reprogramming, nanoparticle-based combination therapies, metabolic checkpoint interventions, and targeted signaling pathway inhibitors. These insights advance the "seed and soil" hypothesis in brain metastasis and support the development of precision therapies targeting the microenvironment to improve outcomes for patients with NSCLC and BM.

Mesenchymal stem cells (MSCs) exhibit remarkable plasticity, capable of adopting either pro-inflammatory (MSC1) or anti-inflammatory (MSC2) phenotypes in response to microenvironmental cues. This review explores their dual role in cancer progression and suppression, immunomodulation of innate and adaptive immune cells, and therapeutic potential in inflammatory diseases. We systematically categorize and evaluate strategies to deterministically program MSC immunophenotypes, bridging canonical approaches (e.g., cytokines and chemokines, Toll-like receptors (TLRs) agonists, autophagy regulators, pharmacological agents, and bacterial components) with emerging non-canonical stimuli (e.g., natural and inorganic compounds, metal ions, engineered biomaterials, and patient-derived immunological components). These approaches provide new strategies to improve MSC-based therapies for cancer immunotherapy and regenerative medicine. While MSC2 phenotypes show promise in treating autoimmune and inflammatory disorders, MSC1 polarization presents opportunities for anti-tumor therapy, either alone or in combination with chemotherapy. However, context-dependent effects of stimuli underscore the need for precise mechanistic understanding. Challenges remain in standardizing protocols, optimizing dosing regimens, and ensuring clinical translation. Future research should focus on elucidating signaling crosstalk, developing GMP-compatible preconditioning methods, and validating combination therapies in complex tumor microenvironment (TME) models. By integrating emerging technologies-such as single-cell analysis and biomaterial engineering-with established approaches, this review highlights pathways toward personalized MSC-based therapies, bridging the gap between experimental innovation and clinical application in inflammation, cancer, and tissue repair.

This bibliometric analysis maps the global research landscape on asthma-cancer associations (2000-2025) using 378 publications. The field is led by the United States (36%) and China (22%), with keyword co-occurrence revealing four research axes: pulmonary disease links, chronic inflammation, allergy-immunity pathways, and notably underdeveloped molecular mechanism studies. We address the central "asthma paradox"-contradictory reports of asthma as a risk, protective, or neutral factor for various cancers-by synthesizing mechanistic hypotheses. A key insight is the dynamic balance between cancer-promoting and -suppressing forces. For example, TGF-β exhibits dose-dependent duality: tumor-suppressive at low levels, but promoting immune evasion and metastasis at high concentrations characterized by severe neutrophilic asthma. Drug repurposing candidates (e.g., montelukast, ciclesonide) show anti-proliferative activity, confirming shared pathogenic pathways. We identify two primary sources of inconsistency: uncontrolled confounders (e.g., smoking) and, critically, the failure to account for asthma heterogeneity. Th2-high (allergic) and Th2-low (non-allergic/neutrophilic) endotypes likely exert divergent effects on cancer risk and progression. Current research remains predominantly epidemiological (53.5%), with mechanistic studies (16.1%) limited by these factors. To advance from associative observations to causal understanding, the study calls for future research to adopt a precision medicine framework. This includes stratifying patients by asthma endotype in large, prospective cohorts and integrating single-cell multi-omics, Mendelian randomization, and real-world data to elucidate the context-dependent molecular mechanisms, such as the dual role of TGF-β, and to validate promising drug repurposing candidates like montelukast.

Regenerative cells, also known as stem cells, exhibit transitioning between a resting state, crucial for long-term preservation with low metabolic activity, and an activation state defined by active proliferation and differentiation to repair old or damaged cells. Concomitant with stem cell transition, mitochondria also undergo a similar transition to support cell growth by providing energy and growth precursors. High mitochondrial activity during cell growth, however, results in reactive oxygen species (ROS). ROS function as signaling molecules and activate several metabolic pathways by rewiring key enzymes and proteins. During the resting state, often called quiescence, ROS production should be limited to prevent resumption of inappropriate growth and oxidation of essential components like DNA in a cell type whose main function is to divide and pass its genetic material to daughter cells for repair. Most stem cells in a resting state (also known as G0 phase) display reduced mitochondrial activity by suppressing oxidative phosphorylation (OXPHOS) due to active mitophagy maintained by quiescence regulators in cells. Mitogens and injury markers activate resting or quiescent stem cells to reenter the cell cycle and grow, a process that requires mitochondrial activity for the supply of nucleotides, non-essential amino acids, lipids and many more. Mitochondria undergo cell cycle-specific changes during the G1, S, and G2/M phases. This article examines how mitochondria regulate stem cell growth and control cell fate. Stem cell dysfunction leads to regeneration issues, contributing to premature aging and cancer. Understanding mitochondrial function can further enhance therapeutic interventions in cancer and aging, as highlighted at the end of the review.

Central nervous system tumors represent a heterogeneous group of diseases, mainly localized in the brain. Among them, malignant brain tumors represent some of the most aggressive cancers. In adults, only approximately 30% of patients diagnosed with glioblastoma survive beyond two years. Similarly, several pediatric-predominant brain tumors, including medulloblastoma, diffuse intrinsic pontine glioma, and ependymoma, remain among the deadliest solid tumors in children. Therefore, a deeper understanding of brain tumor biology is imperative for the development of more effective therapeutic strategies. Dysregulated epigenetic control has emerged as a critical driver of brain tumor initiation and progression, influencing malignant phenotypes across multiple stages of the disease. Epigenetic mechanisms, including DNA methylation, histone modifications, chromatin remodeling, and non-coding RNAs, regulate gene expression programs that contribute to all hallmarks of cancer by modulating the activity of tumor suppressor genes and oncogenes. Given the central role of epigenetics in brain tumorigenesis and the potentially reversible nature of these alterations, epigenetic mechanisms represent particularly attractive therapeutic targets. Although several epigenetic drugs have shown promising results in preclinical and clinical studies, their clinical application remains constrained by a limited knowledge of the brain tumor epigenome and by challenges related to tumor location and drug delivery. In this review, we summarize key epigenetically regulated genes and dysregulated microRNAs across major brain tumor types and link these alterations to specific cancer hallmarks. We further highlight representative examples of epigenetic therapies whose effects converge on hallmark-associated oncogenic processes.

KIAA0101, also known as proliferating cell nuclear antigen (PCNA) clamp-associated factor (PCLAF), is a small PCNA-interacting protein linking DNA replication, DNA damage tolerance, cell-cycle progression, and genome maintenance. Aberrant KIAA0101 expression occurs across multiple human malignancies and is frequently associated with aggressive clinicopathological features, therapy resistance, and poor survival. Beyond its canonical role as a proliferation-associated PCNA cofactor, emerging evidence obtained from bulk transcriptomics, single-cell sequencing, and spatially resolved analyses suggests that KIAA0101-high tumor states mark proliferative, stem-like, immune-excluded, and treatment-resistant ecosystems. However, research in this field remains limited by descriptive correlations, small retrospective cohorts, isoform-blind assays, and incomplete mechanistic validation. In this review, we synthesize current evidence on the structural features, regulatory networks, cellular functions, disease-specific roles, immune-microenvironmental associations, and translational relevance of KIAA0101 in cancer. We emphasize that its immune-related effects are more plausibly mediated through indirect regulatory routes, including NF-κB- and Wnt/β-catenin-associated programs, rather than through the direct transcriptional control of immune checkpoint genes. We further discuss therapeutic strategies targeting the KIAA0101-PCNA interface, KIAA0101 degradation, RNA interference/CRISPR-based suppression, and rational combinations with DNA damage response inhibitors or approved targeted agents. Future work should prioritize isoform-resolved detection, non-PCNA interactome mapping, immune-competent functional models, and biomarker-driven validation to determine whether KIAA0101 can be advanced from a cancer-associated molecule to a clinically actionable biomarker or therapeutic vulnerability.

Breast cancer has emerged as the most prevalent malignant tumor among women worldwide. Its intricate and highly heterogeneous pathogenesis presents substantial challenges for effective treatment. In recent years, the increasing prominence of tumor immunotherapy has highlighted the pivotal role of protein glycosylation, particularly its regulation of glycan structural alterations in the initiation, progression, and immune evasion mechanisms of breast cancer. Evidence suggests that glycan modifications-such as N-glycosylation, O-glycosylation, fucosylation, and sialylation-not only significantly influence tumor cell biology but also directly modulate the function and stability of key immune checkpoint molecules, including PD-1/PD-L1, CD24, and members of the B7 family. Aberrant glycosylation in breast cancer cells fosters the establishment of an immunosuppressive microenvironment, a critical factor that limits the efficacy of immunotherapy. Consequently, interventions targeting glycosylation modifications present promising strategies to enhance the therapeutic response to immunotherapy in breast cancer patients. Thus, our comprehensive exploration of the underlying mechanisms of glycosylation modifications in breast cancer immunotherapy provides a robust theoretical foundation and identifies novel intervention targets to overcome the therapeutic challenges faced in breast cancer and other immunologically "cold" tumors.

Cell chirality is a newly discovered cellular characteristic that is phenotype-specific and is associated with cell migration, cell differentiation, organelle positioning, and organ asymmetry. The maintenance of normal cellular chirality is fundamental for preserving physiological functions in organisms. In recent years, cellular chirality has been increasingly investigated in tumor research, especially metastasis. During tumor metastasis, tumor cells acquire migratory and invasive capabilities through epithelial-mesenchymal transition (EMT), a process that is intricately linked to the dynamic reprogramming of cell chirality. The alterations in the chirality of both tumor cells and other surrounding cells significantly enhance metastatic efficiency not only by regulating cell-extracellular matrix interactions, collective migration patterns, and immune escape but also by increasing vascular permeability. This article provides a comprehensive and systematic exploration of the intricate relationship between cell chirality and tumor metastasis. It meticulously summarizes the molecular mechanisms that govern cell chirality, outlines the commonly employed detection methods, and delves into the potential therapeutic strategies targeting cellular chirality. Given the pivotal role of cell chirality in regulating metastasis, further research in this area holds great promise for revolutionizing cancer treatment and is expected to pave the way for the development of novel therapeutic strategies targeting tumor metastasis.

Despite a significant increase in clinical trials for biliary tract cancers (BTCs) over the past decade, progress in precision therapy has been limited by insufficient understanding of treatment strategies and target specificity. Based on 873 clinical trials for BTCs from the Informa database, we conducted an analysis of the geographical distribution, research phase, treatment modalities, and target characteristics for BTCs over the past decade. We further integrated transcriptomic and proteomic data from the Human Protein Atlas (HPA) to evaluate the differential expression of targets in normal and tumor tissues. The specificity and potential of targets were further analyzed. Clinical trials for BTCs exhibited region-specific dominance, with China and the United States accounting for 35% and 32.5% of trials, respectively. Current major breakthroughs in clinical trials involve combination therapies. Globally, chemotherapy combined with targeted therapy is predominant, whereas China primarily focuses on chemotherapy combined with immunotherapy. Hepatic arterial infusion chemotherapy (HAIC) combined with targeted/immunotherapy represents a distinctive treatment strategy in China. Innovative therapies, such as antibody-drug conjugates (ADCs) and cancer vaccines, are primarily in Phase I/II. The VEGF pathway, FGFR fusions, and HER2 amplification have garnered significant attention for clinical translation. CHEK1, ATR, DNMT1, AURKA, and CA9 represent potential targets demonstrating high safety and specificity. This study provides a comprehensive analysis of the clinical trial landscape for BTCs and evaluates the safety and specificity of therapeutic targets, serving as a reference for future BTC research.

Cancer radiotherapy has made significant strides, yet the persistent challenge of tumor radioresistance continues to compromise therapeutic success. This obstacle stems from a multifaceted network of biological mechanisms, including enhanced DNA damage response, checkpoint dysregulation, hypoxia, metabolic reprogramming, and adaptations within the tumor microenvironment. The superior biocompatibility of phytochemicals positions them as promising candidates for combination approaches, and they have gained increasing attention as safer and mechanistically diverse radiosensitizers. Five major classes of phytochemicals, including coumarins, flavonoids, alkaloids, polyphenols, and terpenoids, are systematically reviewed. Promising radiosensitizing effects have been reported for coumarins, such as auraptene and osthole, as well as for flavonoids, including quercetin, luteolin, and apigenin. The repertoire of natural radiosensitizers is further expanded by alkaloids, such as piperlongumine and berberine, polyphenols, like curcumin and resveratrol, and terpenoids, such as thymoquinone. Despite encouraging preclinical findings, several consistent and critical limitations have been identified across the literature, including the absence of standardized efficacy metrics, heterogeneity in experimental designs, sparse in vivo validation, and unaddressed questions regarding normal cell selectivity. Consequently, clinical validation remains nascent, with only a few early-phase trials having investigated flavonoid-based formulations. By critically synthesizing current evidence and identifying translational gaps, this review provides a foundation for the future development of phytochemical radiosensitizers as viable adjuncts in multimodal cancer therapy.

High-mobility group box 1 (HMGB1), a protein with context-dependent pro- and anti-tumor functions, is expressed in tumor cells, tumor-associated macrophages, tumor-associated neutrophils, cancer-associated fibroblasts, and T cells within the tumor microenvironment. The identity of HMGB1 has undergone a transformation from a nuclear architectural protein to a secreted damage-associated molecular pattern with pivotal roles in inflammation and cancer. The heterogeneity of HMGB1 stems from the diversity of post-translational modifications, proteolytic cleavage and lysis, partial independence of domain functions, differences in source tissues and cells, concentration-dependent effects, spatiotemporal distribution and dynamics, and functional diversity. This review summarizes the roles and molecular mechanisms of nuclear, cytoplasmic, and extracellular HMGB1 derived from different cells in tumor progression, its targeted therapy, and its application value as a biomarker, highlighting the regulation of HMGB1 and the downstream signaling pathways of HMGB1. HMGB1 mainly exerts pro-tumor effects during tumor progression via multiple downstream pathways (MAPK, NF-κB, PI3K/AKT, Wnt, STAT3, etc.), while its subtle induction of cell death and enhancement of the immune response demonstrate moderate anti-tumor effects. HMGB1-mediated immune crosstalk regulates the proliferation, growth, migration, invasion, and chemoresistance of tumors. A comprehensive investigation of the spatiotemporal dynamics of HMGB1 and its underlying molecular regulatory mechanisms using cutting-edge technologies, including single-cell RNA sequencing, spatial transcriptomics, and real-time live-cell imaging, will facilitate the development of precise, mechanism-informed therapeutic interventions. Given the multifaceted challenges posed by tumor heterogeneity, the dual pro- and anti-tumor functions of HMGB1, and the limitations of targeting technologies, HMGB1-targeted strategies hold substantial promise for clinical translation.

Tumor heterogeneity is a fundamental feature of malignant tumors and a major driver of treatment resistance, ultimately contributing to treatment resistance, therapeutic failure, disease recurrence, and poor outcome. Rather than being static, heterogeneity arises early during tumorigenesis and continues to evolve during progression, metastasis, and therapeutic selection. Advances in single-cell and spatial omics, integrative multi-omics profiling, liquid biopsy, and computational modeling have markedly improved the characterization of heterogeneity across genetic, epigenetic, transcriptomic, phenotypic, and microenvironmental dimensions. However, translating heterogeneity profiling into routine clinical decision-making remains challenging due to sampling bias, technical variability, data-integration complexity, and the need for prospectively validated, actionable metrics. In this review, we summarize the biological origins and major classifications of tumor heterogeneity, discuss current approaches for its detection and longitudinal monitoring, examine its implications for established and emerging therapies, and highlight precision-oncology strategies aimed at anticipating, tracking, and ultimately exploiting heterogeneity to achieve durable cancer control.

Neural-tumor interactions have emerged as critical drivers of metabolic reprogramming in cancer. This review systematically examines how neural signaling reshapes tumor metabolism through a conceptual framework that classifies neural-tumor crosstalk into three principal modes: direct physical contacts, paracrine signaling, and indirect mediation via immune and glial cells. Key neurotransmitters (norepinephrine, acetylcholine, glutamate) and neurotrophic factors (NGF, BDNF) engage specific receptors on tumor cells, activating downstream signaling cascades that regulate glycolysis, lipid synthesis, and amino acid metabolism. Central to this axis is lactate, which not only fuels tumor growth but also drives histone lactylation, an epigenetic modification that links metabolic flux to sustained transcriptional reprogramming. Beyond the lactate-centered model, emerging mechanisms-including mitochondrial transfer via tunneling nanotubes, extracellular vesicle-mediated metabolic hijacking, and direct nutrient supply by neurons-reveal the remarkable diversity of neural-driven metabolic regulation. The neuro-immune-metabolic circuit adds another layer of complexity, whereby neural signals reprogram immune cell metabolism to create an immunosuppressive microenvironment. This review further evaluates therapeutic strategies targeting the neural-metabolic axis, from repurposed β-blockers to Trk inhibitors and metabolic interventions. By integrating these multifaceted interactions into a unified framework, we highlight future research directions and therapeutic opportunities that may yield novel treatments targeting the neural-metabolic interface in cancer.

Microfluidic organ-on-chip (OoC) technologies have emerged as reliable platforms for the physiologically accurate simulation of human tumours by precisely modulating cellular, biochemical, and biomechanical parameters. This review critically examines recent advancements in organ-on-chip (OoC) systems for applications in precision oncology, immuno-oncology, preclinical drug discovery, therapeutic response assessment, and mechanistic studies of therapeutic resistance. Unlike traditional preclinical models, OoC systems integrate patient-derived tumour tissues, stromal and immunological components, and three-dimensional microenvironments to more accurately reflect tumour heterogeneity and therapeutic response. We further explored how these technologies enable the real-time evaluation of drug sensitivity, immunological interactions, hypoxia-driven adaptability, and stroma-mediated resistance, providing functional insights beyond genetic profiling. By incorporating recent developments in patient-derived models, immunooncology, mechanobiology, and clinically relevant drug response prediction, this review underscores the translational and mechanistic significance of OoC technologies, distinguishing it from previous reviews that primarily focused on microfabrication and device engineering. We also address contemporary challenges related to standardisation, regulatory validation, scalability, and reproducibility. Collectively, OoC technologies hold significant potential to advance precision medicine, enhance translational oncology, and reduce reliance on animal models in cancer research.

Drug resistance remains a major barrier to durable responses to chemotherapy, targeted therapy, radiotherapy, and immunotherapy. Mitochondria, once viewed mainly as bioenergetic organelles, are now recognized as adaptive signaling hubs that shape tumor survival under therapeutic pressure. Here, we review how mitochondrial dynamics, metabolic plasticity, redox remodeling, programmed cell death regulation, epithelial-mesenchymal transition, and intercellular mitochondrial transfer collectively drive tumor drug resistance. We highlight that resistant cancer cells exploit mitochondrial flexibility to switch between glycolysis and oxidative phosphorylation, reinforce antioxidant defenses, suppress apoptosis, ferroptosis, and cuproptosis, and remodel the tumor microenvironment through metabolic and immune crosstalk. We further discuss emerging therapeutic strategies targeting mitochondrial vulnerabilities, including OXPHOS inhibition, fusion-fission modulation, redox intervention, BH3 mimetics, ferroptosis/cuproptosis induction, and mitochondria-directed delivery systems. Finally, we propose a mechanism-guided translational framework to advance mitochondria-targeted therapies toward biomarker-driven precision oncology. This integrated perspective may help move mitochondria-targeted therapy from a broad preclinical concept toward biomarker-guided precision strategies for overcoming tumor drug resistance.