Oxidative stress is a pathological condition of redox signaling dysregulation and macromolecular oxidative damage arising from elevated ROS levels. Oxidative stress interacts with tumor cell growth regulation and tumor microenvironment remodeling, and has been a critical hallmark of cancer. Targeting oxidative stress has garnered great attention in cancer therapy development. However, it is still challenging due to the complexity and heterogeneity of oxidative stress regulation across different cancers, and this encourages a comprehensive understanding of the oxidative stress network in cancers to overcome this obstacle. Therefore, we introduced the oxidative stress generation and regulatory network within tumor cells and discussed their roles in both tumor cells and the tumor microenvironment. Subsequently, we summarized the current therapeutic strategies and highlighted emerging clinical applications, providing an up-to-date overview of oxidative stress-based approaches. Particularly, their cross-application with immunotherapy and nanomedicine has provided an excellent opportunity to integrate multiple effects, exhibiting surpassing advantages. This review elaborates on oxidative stress in cancer biology and its therapeutic implications. By integrating current knowledge and the emerging coordination with immunotherapy and nanomedicine, we underscore the potential of oxidative stress-targeting approaches. Future research on overcoming therapeutic resistance and developing compatible platforms to combine multiple approaches will pave the way to cancer elimination.

Glycosphingolipids (GSL) are essential components of the plasma membrane where they are known to play key structural and functional roles and are known to influence molecular processes involved in cancer malignancy, including multi-drug chemoresistance, the epithelial to mesenchymal transition (EMT), and the activation or receptor tyrosine kinases (RTK). Thus, investigating and understanding how GSLs are regulated in cancer and the impact they have on malignancy have important therapeutic potential. In the GSL biosynthetic pathway, one critical regulator of two of the four major branches of GSLs is the gene product of B3GNT5, which produces the precursor for all GSLs in the lactoside and neolactoside series.

Cutaneous squamous cell carcinoma (CSCC) is a prevalent skin cancer with aggressive progression that poses significant challenges, especially in metastatic cases. Single-cell DNA sequencing (scDNA-seq) has become an advanced technology for elucidating tumor heterogeneity and clonal evolution. However, comprehensive scDNA-seq studies and tailored mutation panels for CSCC are lacking.

To develop a deep learning-based MRI model for predicting tongue cancer T-stage.

Loss of polarity is a hallmark of cancer, and the related epithelial-to-mesenchymal transition (EMT) phenotype impacts prognosis and therapy outcomes, particularly in colorectal cancer (CRC). However, the mechanisms and drugs that impact EMT-related morphological changes are understudied, due to the complete failure of typical live/dead 2D high-throughput screens to capture morphology or the lack of robustness of 3D screens. We designed a high-throughput screen using 3D type I collagen cultures of CRC cells to assess morphological changes in colonies and identified several FDA-approved drugs that re-epithelialize CRC colonies. One of these drugs, azithromycin, increased colony circularity, enhanced E-cadherin membrane localization and ZO-1 localization to tight junctions, caused transcriptomic changes consistent with downregulation of EMT, and elevated sensitivity to the chemotherapeutic, irinotecan. A retrospective analysis of patient data demonstrated that the use of azithromycin in patients undergoing treatment for CRC with irinotecan had improved the 5 year survival compared to the chemotherapy alone. These results highlight the importance of morphological screens to identify novel drug candidates and synergistic mechanisms.

Endoscopic submucosal dissection (ESD) is an effective treatment with minimal invasiveness for early gastric cancer (EGC). However, cases undergoing non-curative resection (NCR) may still undergo additional surgical procedures. We aimed to analyze the features of NCR under white light imaging (WLI), and develop a prediction model to assess the risk of NCR before ESD. We retrospectively collected and analyzed WLI and clinicopathological features of 568 EGC patients undergoing ESD between March 2016 and March 2024. A nomogram was developed on 455 patients from the training set after subgroup difference analysis. 91 out of 568 (16.0%) cases had NCR. WLI features including remarkable redness, ulceration, fold convergence, marginal elevation, whitish mucosal change, larger lesions, and Helicobacter pylori (Hp) infection were associated with independent risk factors for NCR. The nomogram based on these features showed good predictive value for NCR, with an area under the curve (AUC) of 0.8095 (95% CI: 0.7538-0.8651) in the training set and 0.7567 (95% CI: 0.6427-0.8707) in the validation set. We developed a nomogram incorporating WLI features that exhibits good predictive performance and could potentially assist in selecting optimal treatment strategies for EGC.

Stromal regulation of cancer dissemination is well recognized, however causal genes remain unidentified. We previously demonstrated that epitheliochorial species have acquired stromal resistance to placental invasion, correlating with reduced rate of cancer malignancies, identifying stromal genes correlating with depth of placental invasion called ELI (Evolved Levels of Invasibility) genes. Similarly, decidualization of human endometrial fibroblasts confers resistance to placental invasion. We hypothesized that both trajectories may convergently use similar pathways, providing an opportunity to identify stromal genes regulating epithelial invasion. We created a gene-set ELI-D1 (ELI-Decidual 1), putatively underlying stromal vulnerability to invasion. ELI-D1 were negatively enriched in T1-T2 stage transition in many human cancers, typically preceding dissemination. We also identified candidate transcriptional regulators underlying variation in ELI-D1 genes across eutherians, functionally showing Nr2f6, and JDP2 can regulate stromal resistance to invasion in human fibroblasts. Our comparative approach provides us with a gene-set linked to stromal vulnerability in human cancers.

To highlight the opportunities and pitfalls of organ-preservation strategies for rectal cancer and to define the clinical circumstances in which radical total mesorectal excision (TME) remains imperative, particularly when treatment is delivered outside referral centres.

To assess the prognostic relevance of androgen receptor (AR) expression in patients following modified radical surgery for invasive breast cancer.

Immunosenescence, the age-related decline in immune function, profoundly impacts cancer progression and therapeutic outcomes by fostering a tumor-promoting microenvironment and impairing immune surveillance. This review delineates eleven molecular hallmarks of immunosenescence, including genomic instability, telomere attrition, epigenetic dysregulation, mitochondrial dysfunction, and chronic inflammation, which collectively drive immune cell dysfunction and systemic immunosuppression. Aging reshapes the tumor microenvironment (TME) through recruitment of immunosuppressive cells, senescence-associated secretory phenotypes (SASP), and metabolic reprogramming, contributing to therapy resistance and poor prognosis in elderly patients. While immunotherapies such as immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T-cell immunotherapy (CAR-T) cells show promise, their efficacy in aging populations is limited by T cell exhaustion, myeloid bias, and altered intercellular communication. Emerging strategies-including senolytics, epigenetic modulators (e.g., histone deacetylase (HDAC) inhibitor), and metabolic interventions (e.g., spermidine, nicotinamide mononucleotide (NMN))-highlight potential avenues to rejuvenate aged immunity. Single-cell multi-omics (single cell RNA-seq, single cell ATAC-seq) further unravel immune cell heterogeneity, revealing tissue-specific chromatin accessibility dynamics and novel targets like interleukin-34 (IL-34) for microglia-mediated neuroinflammation. However, challenges persist in translating preclinical findings to clinical practice, necessitating age-tailored trials and biomarker-driven approaches. By integrating mechanistic insights with translational innovations, this review underscores the urgency of addressing immunosenescence to optimize cancer immunotherapy for aging populations, ultimately bridging the gap between aging biology and precision oncology.

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway senses cytosolic DNA and triggers innate immune responses. Pharmacological activation of the cGAS-STING pathway by cGAS-STING agonists to overcome cancer drug resistance offers substantial potential to promote antitumor immunity. However, small-molecule STING agonists show rapid excretion, low bioavailability, non-specificity, and adverse effects, which limit their therapeutic efficacy and in vivo applications. The recent emergence of nanomedicine has profoundly revolutionized STING agonist delivery, promoting tumor-targeted delivery and offering new opportunities for tumor-specific immunotherapy. A growing body of evidence has shown that cGAS-STING interacts with ferroptosis in cancer cells. Targeting the interplay between cGAS-STING and ferroptosis using nanomedicines offers a novel cancer treatment regimen. In this review, we outline the principal components of the cGAS-STING signaling cascade and discuss its role in cancer biology. We also review the role of the interplay between cGAS-STING and ferroptosis in cancer genesis. We then focus on providing an overview of the latest findings and emerging concepts that leverage the interplay between cGAS-STING and ferroptosis by nanomedicine to kill cancers. Finally, we discuss the key limitations of the current therapeutic paradigm and possible strategies to overcome them. This article highlights some promising therapeutic avenues that leverage the interplay of cGAS-STING and ferroptosis by nanomedicine, which could be used to treat cancer.

Circulating tumor cells (CTCs), which serve as an early indicator of tumors in peripheral blood, are closely associated with unfavorable prognoses in individuals with cancer. Gaining a thorough understanding of the heterogeneity and specific trajectory of CTCs during metastasis can yield valuable insights for the development of effective cancer treatment strategies. This review critically examines the contemporary knowledge of the in vivo process of CTCs, with a focus on the four key stages: dissemination, homing, colonization, and macro-metastasis. Each stage is discussed in terms of its associated characteristics, including epithelial-mesenchymal transition (EMT), dormancy, organotropism, and awakening. We also discuss recent advancements in CTC isolation, detection, cultivation and its potential applications. Additionally, it provides a comprehensive elucidation of the intricate mechanisms of immune evasion and drug resistance in CTCs, aiming to identify novel targets for cancer therapy. Finally, an overview of CTC interventions is presented, which may facilitate the development of personalized therapeutic approaches for patients and improve their metastasis-free prognostic outcomes.

Clear cell renal cell carcinoma (ccRCC) commonly exhibits biallelic inactivation of VHL genes, profoundly impacting intracellular metabolic pathways and utilization of metabolic substrates. The aims of this study were to validate the metabolomic profile previously identified in ccRCC surgical specimens, to construct a metabolic classification in ccRCC, and to exploratorily investigate metabolic biomarkers of systemic therapy response.

Collagen type VI alpha 6 chain (COL6A6), an essential component of epithelial cell basal lamina, is hypothesized to function as a tumor suppressor in various cancers, yet its role in breast cancer remains unclear. This study aimed to elucidate COL6A6 expression patterns, assess its impact on the tumor immune microenvironment, and uncover underlying molecular mechanisms in breast cancer progression.

We designed our study with the aim of conducting a comprehensive analysis of the role that GDF-15 plays in pan-cancer. Multiple databases were used to obtain GDF-15 expression. XIANTAO Academic and Sangerbox were utilized to conduct the diagnostic significance of GDF-15 expression across pan-cancer. The relationships between GDF-15 expression and clinical data, tumor stemness, genomic instability, and tumor prognosis in pan-cancer were evaluated. The interaction between molecules and RNA methylation phenotypes related to GDF-15 were explored. The correlations between GDF-15 expression and immune cell infiltration, immune-related genes, as well as immune checkpoints were also under investigation. Besides, immunohistochemistry (IHC)-based tissue microarray analysis of LUAD validated GDF-15 protein expression and its correlation with survival prognosis. GDF-15 exhibited differential expression across various cancers, being upregulated in BRCA, CHOL, COAD, HNSC, LIHC, LUAD, READ, STAD, THCA, and UCEC, but downregulated in KIRC and LUSC. Its expression correlated with clinical parameters and GDF-15 expression had prognostic value in some cancers. Notably, it had a remarkable diagnostic value in CHOL, COAD, ESCC, GBM, LAML, READ and THCA. GDF-15 was involved in influencing tumor stemness, genomic instability. Besides, GDF-15 interacted with molecules involved in iron ion homeostasis and acute-phase response, receptor activator, ligand activities and cellular senescence. It was intertwined with key tumor processes. Moreover, GDF-15 expression further influenced immune cell infiltration, related immune genes, and immune checkpoints. More importantly, IHC staining results of tissue microarrays confirmed its differential protein expression in LUAD tissues, where elevated levels were significantly associated with poorer overall survival, underscoring its clinical relevance. GDF-15 functioned as a prospective indicator for both the diagnosis and prognosis in various cancers.

Dysregulated expression of circular RNAs (circRNAs) has been implicated in the initiation and progression of various diseases, including cancer. In this study, we investigated the role of hsa_circ_0005571 in modulating the biological characteristics of colorectal cancer (CRC) cells. Initially, the circRNA expression profiles of CRC tissues and corresponding normal tissues were analyzed using bioinformatics to identify differentially expressed circRNAs. Subsequently, quantitative real-time PCR (qRT‒PCR) was used to validate the expression levels of hsa_circ_0005571 in both CRC tissues and cell lines. In vitro assays, including the Cell Counting Kit-8 (CCK-8), colony formation, 5-ethynyl-2'-deoxyuridine (EdU) incorporation, wound healing, and Transwell invasion assays, were employed to assess the effects of hsa_circ_0005571 on CRC cell proliferation and invasion. Additionally, tumorigenic potential was examined through in vivo tumorigenesis experiments in nude mice. Bioinformatic predictions and experimental evidence indicated that hsa_circ_0005571 may function as a sponge for miR-520f-3p, which was found to be downregulated in CRC cells. Moreover, LRP8 was predicted and confirmed as a direct downstream target of miR-520f-3p, with both the mRNA and protein levels of LRP8 significantly elevated in CRC cells. Overall, our results suggest that hsa_circ_0005571 enhances CRC proliferation and invasion by modulating the miR-520f-3p/LRP8 axis. Furthermore, elevated hsa_circ_0005571 expression in CRC tissue samples and cell lines relative to that in normal controls was positively correlated with metastasis (p = 0.029) and advanced clinical stage (p = 0.006). Survival analyses revealed that CRC patients with high levels of hsa_circ_0005571 expression had significantly lower overall survival rates than did those with low expression (p < 0.05). Functional assays confirmed that hsa_circ_0005571 facilitates CRC cell proliferation and migration, whereas its knockdown results in reduced migration, proliferation, and tumorigenic potential in vivo. Finally, Western blot analyses demonstrated that LRP8 expression varied in accordance with the levels of hsa_circ_0005571 and miR-520f-3p, further confirming the involvement of the hsa_circ_0005571/miR-520f-3p/LRP8 regulatory axis in CRC. Our study suggested that hsa_circRNA_0005571 promotes proliferation and migration through the miR-520f-3p/LRP8 axis in CRC. Consequently, hsa_circ_0005571 may represent a promising novel gene target for the diagnosis and treatment of CRC.

Lymph nodes (LNs) play a pivotal role in colorectal cancer (CRC) progression and immunity, yet their molecular and functional diversity remains poorly understood. By analyzing 630 LNs and 88 primary tumors from 200 CRC patients across four independent cohorts using bulk and single-cell RNA sequencing, we identify four non-metastatic negative LNs (NLN) subtypes (NLN_C1-C4) exhibiting obviously different immune function and stromal expansion. NLN_C3/C4 are characterized by diminished T and B cell activity and fibroblast-driven fibrosis, with follicular dendritic cell loss contributing to B cell dysfunction. Immune checkpoint inhibitors partially reverse these effects, restoring FDC and B cell activity. LNs subtypes demonstrate heterogeneity across patients and within individuals, with higher NLN_C3/C4 proportions associated with advanced tumor stages, poorer survival, and recurrence. Here, we report LNs subtypes as critical manifestations of LN heterogeneity in CRC, providing a basis for improved clinical stratification and LN-targeted therapeutic strategies.

Target identification in natural products plays a critical role in the development of innovative drugs. Bufalin, a compound derived from traditional medicines, has shown promising anti-cancer activity; however, its precise molecular mechanism of action remains unclear. Here, we employ artificial intelligence, molecular docking, and molecular dynamics simulations to elucidate the molecular mechanism of Bufalin. Using an integrated multi-predictive strategy, we identify CYP17A1, ESR1, mTOR, AR, and PRKCD as the potential targets of Bufalin. Subsequent validation via surface plasmon resonance, biotin pulldown, and thermal shift assays confirms Bufalin's direct binding to ESR1, which encodes estrogen receptor alpha (ERα). Molecular docking analyses pinpoint Bufalin's selective interaction with Arg394 on ERα. Molecular dynamic simulations further show that Bufalin acts as a molecular glue, enhancing the interaction between ERα and the E3 ligase STUB1, thereby promoting proteasomal degradation of ERα. Given the therapeutic potential of ERα degradation in overcoming endocrine resistance, we investigate the inhibitory effect of Bufalin on endocrine-resistant models and prove Bufalin reverses Tamoxifen resistance in vitro, in vivo, and in patient-derived breast cancer organoids from tamoxifen-relapsed cases. Collectively, our findings indicate that Bufalin functions as a molecular glue to degrade ERα, offering a potential therapeutic strategy for reversing Tamoxifen resistance.

SETD1A is a member of the KMT2 histone H3K4 methyltransferase family of mammalian proteins. Aberrant SETD1A expression is associated with a poor prognosis in patients with gastric cancer (GC). We found that the catalytic domain of SETD1A is nonessential for GC cell proliferation, whereas the non-catalytic FLOS domain is essential. The loss of SETD1A commonly reduces the expression of E2F target genes in GC cell lines from the three independent molecular subtypes. A pooled CRISPR screen and cDNA rescue experiment showed that TAF6 acts downstream of SETD1A's non-catalytic function, which is essential for GC cell proliferation. Both SETD1A and TAF6 are required for G1/S cell cycle progression in GC cells. The mRNA expression of E2F4 highly correlated with both the SETD1A and TAF6 expression in patients with GC. Notably, E2F4 supported the expression of TAF6 but not that of SETD1A, suggesting that E2F4 serves as a coregulator of SETD1A, which is involved in regulating TAF6. These results demonstrate that the non-canonical roles of SETD1A and its downstream pathways are crucial for cell cycle progression in GC.

While dysregulation of polyamine metabolism is frequently observed in cancer, it is unknown how polyamines alter the tumor microenvironment (TME) and contribute to therapeutic resistance. Analysis of polyamines in the plasma of pancreatic cancer patients reveals that spermine levels are significantly elevated and correlate with poor prognosis. Using a multi-omics approach, we identify Serpinb9 as a vulnerability in spermine metabolism in pancreatic cancer. Serpinb9, a serine protease inhibitor, directly interacts with spermine synthase (SMS), impeding its lysosome-mediated degradation and thereby augmenting spermine production and secretion. Mechanistically, the accumulation of spermine in the TME alters the metabolic landscape of immune cells, promoting CD8+ T cell dysfunction and pro-tumor polarization of macrophages, thus creating an immunosuppressive microenvironment. Small peptides that disrupt the Serpinb9-SMS interaction significantly enhance the efficacy of immune checkpoint blockade therapy. Together, our findings suggest that targeting spermine metabolism is a promising strategy to improve pancreatic cancer immunotherapy.