Background: Breast cancer has the highest incidence among all cancers in women, and the prognosis of breast cancer is strongly linked to the stage of the disease. As one of the components found in liquid biopsy samples, exosomes are membranous vesicles that are actively secreted by living cells. Therefore, the key genes in exosomes may serve as biomarkers for predicting the prognosis of breast cancer patients. Methods: In this study, 128 blood samples collected from breast cancer patients at Fudan University Shanghai Cancer Center between June 2018 and March 2019 were subjected to transcriptome sequencing, and the resulting dataset was used as the training dataset. A LASSO regression model was employed for screening prognostic genes. Additionally, 131 patient samples from February 2020 to February 2022 were collected to establish the validation dataset. The corresponding phenotypes and mechanisms of the key genes were confirmed by CCK8 cell proliferation, colony formation, EdU cell proliferation, flow cytometry, transwell cell migration, scratch assay, animal study and RNA-seq assays. Results: Eleven differentially expressed genes tended to increase from the benign stage to the late stage of breast cancer. Five genes were further identified by LASSO regression analysis to establish a prognostic model. The time-dependent receiver operating characteristic (ROC) curves revealed area under the curve (AUC) values of 0.858 for the 1-year follow-up and 0.772 for the 2-year follow-up. The time-dependent ROC curve of the validation dataset indicated an AUC value of 0.840 for the 1-year follow-up. JCAD, a gene closely associated with prognosis, was selected for further investigation. The experimental results demonstrated that JCAD may activate the Wnt/β-catenin pathway by increasing FZD1 expression, thereby promoting the EMT process and breast cancer progression. Conclusions: Exosomal JCAD, as a prognostic marker, plays an important role in the diagnosis and treatment of breast cancer.

Background: Lipid reprogramming represents a pivotal stage in tumor progression. N6-methyladenosine (m6A), the most prevalent RNA modification in eukaryotic cells, plays a significant role in colorectal cancer (CRC) development, though its specific involvement in lipid reprogramming remains unclear. Methods: Bioinformatics analysis of The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases revealed differential expression of METTL16 (M16), which was further validated through qRT-PCR and Western blotting in CRC tissues and cell lines. The impact of M16 on CRC proliferation, metastasis, invasion, and lipid reprogramming was evaluated using both in vivo and in vitro approaches. Regulatory mechanisms underlying M16's role in CRC progression were explored using immunofluorescence (IF) staining, RNA immunoprecipitation (RIP), MERIP assay, RNA pull-down assay, total m6A measurement, RNA stability assay, protein stability analysis, and luciferase reporter assays. Results: Analysis results demonstrated a significant upregulation of the m6A methyltransferase METTL16 in CRC, closely associated with poor prognosis and abnormal lipid droplet accumulation. Functional assays revealed that M16 overexpression markedly promotes CRC cell proliferation, migration, and invasion both in vitro and in vivo, primarily by enhancing lipid reprogramming. Mechanistically, M16 induces m6A modification of TM7SF2 mRNA, stabilizing it via an IGF2BP1- and IGF2BP2-dependent pathway, thereby upregulating TM7SF2 expression and driving lipid reprogramming in CRC. Conclusion: In conclusion, these findings highlight the critical role of the M16/m6A/TM7SF2 axis in lipid metabolic reprogramming in CRC, offering potential therapeutic targets for its treatment.

Long non-coding RNAs (lncRNAs) have emerged as key regulators of cancer progression through their interaction with microRNAs and modulation of gene expression. However, their role in mitochondrial metabolism, particularly in non-small cell lung cancer (NSCLC), remains poorly defined. In this study, we found that LINC02802 was significantly upregulated in NSCLC tissues and associated with poor prognosis. Mechanistically, LINC02802 acts as a competing endogenous RNA (ceRNA) for miR-1976, thereby relieving the suppression of solute carrier family 25 member 51(SLC25A51). Elevated SLC25A51 enhances mitochondrial NAD+ import, leading to an increased NAD+/NADH ratio and promoting oxidative TCA cycle flux. Functionally, this shift supports tumor cell proliferation and migration. Rescue experiments confirmed that the oncogenic effect of LINC02802 is dependent on the miR-1976/SLC25A51 axis. Interestingly, either silencing LINC02802 with antisense oligonucleotides (ASOs) or treating cells with fludarabine phosphate, an SLC25A51 inhibitor, successfully reversed cisplatin resistance in lung cancer cells. Our findings reveal a novel lncRNA-microRNA-metabolic axis wherein LINC02802 facilitates NSCLC progression by reprogramming mitochondrial metabolism via miR-1976-mediated upregulation of SLC25A51. Targeting this axis may offer therapeutic potential for metabolic intervention in NSCLC.

Background: Despite advancements in EGFR- and KRAS-targeted therapies for lung adenocarcinoma (LUAD), novel targets are needed for patients unresponsive or resistant to current treatments. This study demonstrates the critical role of CREPT in modulating ERK-downstream gene transcription in LUAD progression. Methods: CREPT expression and function were investigated using human LUAD tissues, EGFR/KRAS mutant LUAD cell lines, and mouse models. Micro-CT was used to monitor tumor progression. Adeno-associated virus (AAV)-mediated CREPT depletion was employed as a therapeutic strategy. RNA sequencing and luciferase reporter assays identified differentially expressed genes (DEGs) and affected signaling pathways. Protein interactions and CDK9 occupancy were assessed using multiplex immunofluorescence, immunoprecipitation, and chromatin immunoprecipitation (ChIP). Results: CREPT overexpression correlated with poor LUAD patient survival and enhanced tumorigenesis in EGFR or KRAS mutant LUAD cells. CREPT deletion impaired LUAD initiation and progression in the CC10-rtTA;TetO-KRASG12D mouse model. Mechanistically, CREPT promoted CDK9 assembly with RNA polymerase II (RNAPII) following ERK activation, enhancing transcription of malignancy-related genes downstream of KRAS-ERK-Elk-1 signaling. CREPT depletion and the mutants R106A and S134A disrupting CREPT-RNAPII interaction reduced CDK9 occupancy at Elk-1 downstream gene promoters and their expression. Targeting CREPT in both CC10-rtTA;TetO-KRASG12D and xenograft mouse models resulted in tumor growth arrest. Furthermore, in a humanized mouse model, AAV-mediated CREPT silencing inhibited tumor progression and showed synergistic potential with pembrolizumab. Conclusion: Our findings highlight CREPT as a pivotal regulator of LUAD progression and suggest it could be a potential therapeutic target for patients with EGFR or KRAS mutations insensitive or resistant to targeted therapies.

Rationale: Gastric cancer (GC) with ovarian metastasis (OM) represents a distinct subtype of peritoneal metastasis in female patients, characterized by limited therapeutic options and poor prognosis, with molecular features and mechanisms that remain unknown. Methods: We performed whole-exome sequencing (WES) analysis of matched GC samples, with OM or peritoneal metastasis (PM), to identify mutational profiles that contribute to OM. We further validate these findings through in vitro and in vivo experiments. Results: We characterized specific mutated genes in GC with OM, including FLCN, DNAJC13, DSC3, SLC9A3, ADGRV1, SCAPER, and ARHGEF12. Moreover, these genomic mutations are recurrent in both GC and ovarian cancer. We further identified the E620K mutation of ARHGEF12, a Rho guanine nucleotide exchange factor, as a novel risk locus in GC with OM. Ectopic expression of the E620K mutant increased cell migration, invasion and colony formation in vitro, as well as OM in animals bearing GC xenograft tumors. Mechanistically, ARHGEF12 E620K mutation upregulated ITGA6 expression through Rap1 signaling pathway activation and promoted tumor-derived ITGA6-high exosome formation, which were preferentially uptaken by ovarian fibroblasts. Reciprocally, ovarian fibroblasts educated by ITGA6-high exosomes exhibited cancer-associated fibroblasts (CAFs) phenotypes and enhanced tumor cell proliferation, thereby initiating the early stage of pre-metastatic niche formation. Conclusions: Our study provides comprehensive clinical exome profiling, identifies ARHGEF12 mutation as a new driver, and reveals that ITGA6 acts as an early predictive marker in GC with OM.

Rationale: Enzalutamide (Enz) is the first-line therapy for castration-resistant prostate cancer (CRPC). However, drug resistance has hindered its further application. Moreover, CRPC is frequently prone to metastasis, particularly to bone (BmCRPC). Methods: To investigate the involvement of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) deletion and C-X-C motif chemokine receptor 2 (CXCR2) overexpression in Enz-resistant CRPC and BmCRPC, we constructed a bisphosphonate (BP) lipid-like material with high bone affinity (GB4-BPL) for the codelivery of a PTEN plasmid (pPTEN) and CXCR2 siRNA (siCXCR2) to BmCRPC. Results: GB4-BPL demonstrated twice the bone metastasis-targeting ability of GB4-lipo (which lacks bisphosphonate modification) while maintaining a gene transfection efficiency comparable to that of Lipo8000 and exhibiting significantly lower cytotoxicity. Moreover, siCXCR2 and pPTEN loaded in GB4-BPL (GB4-BPL@siCXCR2/pPTEN) synergistically inhibited tumor growth and metastasis, highly enhancing the effect of Enz by 69.45% in the Enz-resistant model. Furthermore, GB4-BPL@siCXCR2/pPTEN significantly reduced the numbers of MDSCs, Tregs, and M2-like TAMs by 55.01%, 64.75%, and 52.53%, respectively, while increasing the proportions of M1 macrophages, NK cells, and CD8+ T cells by 1.65-, 1.40-, and 4.60-fold, respectively. In addition, this nanosystem reduced skeletal-related events. Conclusions: Our studies demonstrated the potential of GB4-BPL for delivering siCXCR2/pPTEN to tumor and bone metastatic sites. GB4-BPL@siCXCR2/pPTEN alone or in combination with Enz could provide a new strategy for the treatment of drug-resistant BmCRPC.

Background: Hepatocellular carcinoma (HCC) causes a significant mortality burden worldwide. Radiotherapy (RT) is the primary locoregional treatment modality for HCC. However, the efficacy of RT in HCC is limited by tumor microenvironment (TME) hypoxia, immunosuppression, and extracellular matrix (ECM) stiffness. Methods: We developed a novel RGD-modified liposomal platform (RGD@LP-Y) that encapsulates the ROCK inhibitor Y-27632 through thin-film hydration. We characterized the RGD@LP-Y by the transmission electron microscope (TEM), UV-Vis spectrophotometer, and dynamic light scattering instrument (DLS). A high-stiffness hydrogel co-culture system mimicking mechanical TME was established to explore the role of RGD@LP-Y on matrix stiffness remodeling. In vitro evaluations included cytotoxicity, reactive oxygen species (ROS) generation, mitochondrial function, immunogenic cell death (ICD) markers, and immune cell activation. Mechanistic investigations encompassed matrix stiffness regulation analysis, flow cytometry profiling of pro-inflammatory macrophages, dendritic cell (DC) maturation, transcriptome sequencing, and western blotting. In vivo validation used xenograft models treated with intravenous RGD@LP-Y and localized RT. Biosafety was confirmed through organ histology, serum biochemistry analysis, and hemolysis assay. Results: RGD@LP-Y downregulated matrix stiffness markers (YAP/COL1) and activated PI3K/AKT/NF-κB signaling to drive pro-inflammatory macrophage polarization and DC maturation. The synergistic effects were observed in combination with RT. The treatment of RGD@LP-Y and RT inhibited HCC proliferation, induced apoptosis, suppressed mitochondrial respiration, elevated intracellular ROS, and thus enhanced ICD. In vivo, RGD@LP-Y+RT demonstrated potent tumor suppression and immune activation without systemic toxicity. Conclusion: RGD@LP-Y enhances RT sensitivity by remodeling ECM stiffness, modulating the hypoxia and immunosuppressive conditions within TME, and enhancing the ICD. The study provides a safe combinatorial approach for HCC therapy.

Cancer is an extremely complex disease characterized by abnormal cell growth due to genetic and environmental factors. With the rise of the field of epigenetic transcriptomics, 5-methylcytidine (m5C) modification has been identified as one of the most common chemical modifications occurring in various RNA types. The writers, erasers, and readers of m5C modification regulate cancer initiation, progression, and therapeutic responses, such as the proliferation, metastasis, angiogenesis, metabolic reprogramming, immune escape, and therapeutic resistance of tumour cells, by regulating RNA stability, translation, nuclear export, and splicing processes. In this review, we elucidate the biological process of m5C modification, summarize the abnormal expression of RNA-modifying proteins (RMPs) in common malignant tumours, explore their functional effects on malignant hallmarks of cancer and molecular mechanisms, and prospect the potential clinical application value of m5C.

Rationale: Melanoma remains a highly aggressive malignancy with limited effective therapies and frequent resistance to immune checkpoint blockade (ICB). Extracellular vesicles (EVs) represent a promising platform for RNA-based therapeutics, but their clinical translation is impeded by inefficient cargo loading and insufficient tumor-specific targeting. To address these limitations, we developed an engineered EV strategy integrating efficient miRNA packaging with tumor-targeting surface modifications to enhance therapeutic outcomes in melanoma. Methods: Engineered EVs (iEV-150) were generated by co-expressing miR-150-3p and Annexin A2 (ANXA2) in HEK293T cells, followed by surface modification with tumor-targeting iRGD peptides. Mechanistic insights were obtained using RNA sequencing, RNA immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP), and luciferase reporter assays. Ferroptosis induction was evaluated through lipid peroxidation analysis, mitochondrial membrane potential assays, and transmission electron microscopy (TEM). Therapeutic efficacy and biodistribution were assessed in vivo using subcutaneous and metastatic melanoma mouse models. Immune modulation was examined by analyzing CD8⁺ T cell activation via flow cytometry in co-cultures of patient-derived CD8⁺ T cells and melanoma cells treated with iEV-150. Results: miR-150-3p was elevated in melanoma-derived EVs, and ANXA2 was identified as a key RNA-binding protein that selectively facilitated its loading into EVs. iEV-150 exhibited enhanced uptake by melanoma cells and improved tumor-specific accumulation in vivo. Mechanistically, iEV-150 suppressed NF2 expression, disrupted the NF2-LATS1 interaction, activated YAP signaling, and subsequently upregulated ferroptosis-related genes ACSL4 and CHAC1, thereby inducing ferroptosis through the NF2-Hippo-YAP axis. In addition to its direct anti-tumor effects, iEV-150 promoted CD8⁺ T cell infiltration and activation within the tumor microenvironment, and significantly enhanced the therapeutic efficacy of ICB in melanoma models. Conclusions: iEV-150 integrates ANXA2-mediated miRNA loading, tumor-specific targeting, ferroptosis induction, and immune microenvironment reprogramming. This engineered EV strategy provides an effective RNA-based therapeutic platform to overcome ICB resistance and enhance precision treatment in melanoma.

Single extracellular vesicle (EV) analysis holds great promise for non-invasive cancer diagnostics, offering insights into tumor-specific biomarkers and enabling personalized treatment strategies. However, a significant challenge in the path towards clinical applications is the low abundance of tumor-derived EVs (tEVs) in biofluids, which reduces the sensitivity, specificity, and accuracy of detection. This review emphasizes the importance of analyzing a large number of single EVs to overcome this limitation. We estimate that less than 0.1% of total EVs could be from cancer cells in a mixed sample. Additionally, the development of more efficient tEVs isolation methods and targeted enrichment strategies, as well as high-throughput analysis techniques are crucial for improving diagnostic accuracy and advancing liquid biopsy applications in cancer care.

Cellular senescence is characterized by cell cycle arrest, resistance to apoptosis, the expression of senescence markers, and the acquisition of senescence-associated secretory phenotype (SASP). In this review, we discuss the role of cellular senescence within the tumor microenvironment. Some senescent innate immune cells fail to sustain their antitumor function and may even promote tumor progression. Senescent CD8+ and CD4+ T cells become dysfunctional and are implicated in immunosuppression, angiogenesis, and resistance to immunotherapy. Research on stromal senescence primarily focuses on the SASP. The SASP functions as a double-edged sword. It promotes immune surveillance in the early stages of a tumor while inhibiting tumor immunity in its advanced stages. Strategies to target senescence in cancer therapies include four main approaches: inducing senescence, inhibiting tumor-promoting SASP, clearing senescent cells, and reversing senescence. Although not yet in clinical practice, these approaches hold promise for future cancer treatments.

Rationale: Pyroptosis, a form of programmed cell death mediated by gasdermin proteins, holds significant potential in cancer immunotherapy. However, precise control of pyroptosis in cancer cells is essential to avoid biosafety concerns. This study aimed to develop a tumor-targeted and tunable pyroptosis-inducing strategy to enhance antitumor efficacy while minimizing systemic side effects. Methods: An innovative H2S-activated nanomodulator equipped with an optical switch was designed for tumor-specific and adjustable pyroptosis induction. The nanomodulator was activated by H2S in the tumor microenvironment of colorectal cancer and further regulated by laser irradiation. Gasdermin-E-mediated pyroptosis was triggered through the synergistic effects of photothermal temperature modulation and demethylation. The proportion of cells undergoing pyroptosis was precisely controlled within a tunable range. Results: The nanomodulator successfully induced pyroptosis in microsatellite-stable colorectal cancer cells within a tunable range of 0-31%. This precise regulation significantly enhanced antitumor efficacy while minimizing systemic side effects. The combination of photothermal modulation and demethylation ensured effective and safe pyroptosis induction. Conclusions: This study presents a novel and precise method for controlling pyroptosis using photothermal temperature modulation. The findings provide essential guidance for in vivo applications and offer valuable insights into the development of nanomedicines capable of safely and effectively inducing adjustable proportion of pyroptosis in cancer therapy.

Hypoxia can substantially impact clinical outcomes in patients with head and neck cancer (HNC) by promoting tumor invasion, metastasis, immune escape, and therapy resistance. Given the growing interest in targeting hypoxia for cancer therapy, noninvasive methods are needed to accurately detect hypoxia and evaluate the tumor response to treatment. This review summarizes recent advances in hypoxia-targeted probes and imaging techniques, emphasizing their imaging mechanisms, strengths, and limitations. We focused on the promising clinical applications of hypoxia imaging, especially those currently used in clinics, such as positron emission tomography and magnetic resonance imaging, and highlighted their roles in guiding personalized therapy. Future directions include optimizing imaging probes to improve safety profiles, integrating multimodal imaging, applying machine learning models to analyze multiparametric data, and establishing standardized 3-dimensional in vitro models to better mimic hypoxia heterogeneity. These advancements are expected to considerably improve the management of patients with HNC.

Irisin, a myokine secreted by skeletal muscle, has garnered significant attention for its multifaceted physiological roles and emerging potential as both a biomarker and therapeutic target in oncology. This review consolidates current understanding of irisin's impact across various malignancies, focusing on its complex regulation of tumorigenesis through interactions with key signaling pathways including PI3K/AKT, AMPK-mTOR, and STAT3/Snail. Critically, irisin exhibits a paradoxical dual role: it suppresses proliferation, migration, and invasion in cancers such as lung, breast, and pancreatic carcinoma, yet paradoxically promotes the progression of hepatocellular carcinoma. This tissue-specific dichotomy presents a significant therapeutic challenge. Furthermore, inconsistent findings regarding irisin expression levels even within the same tumor type highlight the urgent need for further mechanistic investigation. Future research must prioritize elucidating the context-dependent mechanisms of irisin within the tumor microenvironment and rigorously evaluating its clinical utility as a biomarker through large-scale trials. Resolving these contradictions is essential for developing a unified understanding of irisin's role in cancer biology. Such insights hold promise for paving the way toward novel therapeutic strategies, potentially enhancing the efficacy of personalized cancer therapy.

Hepatocellular carcinoma (HCC) is a malignant tumor of the liver. Treatment programs according to its physiological and pathological characteristics have reduced the number of new cases and deaths of HCC, but the morbidity and mortality are still high, posing a significant threat to human health. In recent years, the importance of mitophagy in the treatment of HCC has gradually been recognized. The activation of mitophagy inhibits the survival, proliferation and migration of HCC cells through a variety of pathways, promotes cell apoptosis, and can also reduce drug resistance, providing a new direction for the treatment of HCC. Studies have shown that Traditional Chinese medicine (TCM) monomers and their derivatives can improve the therapeutic efficacy of HCC and slow down disease progression by regulating mitophagy. This article summarizes the potential mechanism of mitophagy in the progression of HCC and comprehensively explores the potential of TCM monomers and their derivatives in the treatment of HCC, providing new perspectives and strategies for clinical treatment.

Multiple myeloma (MM) is a clonal plasma cell malignancy characterized by bone marrow infiltration, monoclonal immunoglobulin production, and multisystem damage. Proteasome inhibitors (PIs) such as bortezomib, carfilzomib, and ixazomib have significantly improved progression-free and overall survival in MM patients. However, drug resistance and adverse effects-including peripheral neuropathy and cardiotoxicity-remain major limitations to long-term disease control.

Cervical cancer (CC) exerts a considerable impact on women's health worldwide and presents persistent challenges to conventional therapeutic strategies due to its propensity for distant metastasis, postoperative recurrence, and variable drug resistance. Ferroptosis, a recently identified type of programmed cell death, offers promising potential for a therapeutic approach for CC. This paper reviews the regulatory processes involved in ferroptosis, including the sequential events leading to cell membrane rupture via lipid peroxidation and the changes in ferroptosis sensitivity as cervical cells progress from a healthy to a malignant condition. Additionally, the dynamic relationship between ferroptosis and CC transformation driven by high-risk HPV (HR-HPV) infection is examined, with a particular focus on how HR-HPV E6/E7 proteins influence ferroptosis sensitivity. By examining the factors associated with ferroptosis, this review provides insights into CC progression and prognosis. Furthermore, therapeutic strategies targeting ferroptosis are discussed, offering novel perspectives for effective treatment options for CC.

Synthetic lethality (SL) not only addresses the challenge of drug resistance associated with classical targeted therapies but also offers innovative therapeutic approaches for previously 'undruggable' targets, such as deletion mutations in tumour suppressor genes. Advances in technology have significantly enhanced our understanding of gene-gene interactions in cancer cells, enabling the identification of synthetic lethal targets and the development of drugs targeting these mechanisms. Following the extensive clinical application of PARP inhibitors-the first synthetic lethal targeted drugs approved for clinical use-emerging targets such as ATR, WEE1 and WRN have demonstrated promising clinical potential. This review examines the functions and molecular mechanisms underlying these targets and discusses recent advancements in the theory of synthetic lethality. Additionally, it emphasises the integration of synthetic lethal drugs with traditional cancer treatments, highlighting the clinical benefits of this combined strategy and its potential to facilitate more precise and individualised cancer treatment modalities in the future.

To evaluate the clinical and prognostic significance of immunoglobulin heavy chain (IgH) cytogenetic abnormalities in patients with newly diagnosed multiple myeloma (NDMM) and explore their association with other high-risk cytogenetic features.

Patients undergoing curative treatment for soft-tissue sarcomas (STS) of the thigh bear the risk of developing lymphatic fistula and lymphedema. Innovative microsurgical concepts such as primary preventive lymphatic reconstruction show promising results. To discuss the likelihood of lymphatic complications after limb-preserving treatment of STS in the era before lymphatic reconstructive surgery and depending on the sarcoma location in the thigh became paramount in treating these patients.  Methods: We reviewed clinical data of 471 patients who underwent curative lower limb sarcoma treatment at our institution during the period from 2005 to 2019. We allocated patients into cohorts depending on the tumor location in the thigh respecting anatomical compartments as medial, posterior and the anterior compartment. We primarily analyzed incidences of postoperative lymphatic fistula and lymphedema.