Breast cancer is one of the most prevalent malignancies among women and comprises a heterogeneous spectrum of molecular subtypes with distinct biological behaviors. Among various regulatory molecules, sphingolipids play pivotal roles in dynamically modulating fundamental cellular processes such as proliferation, apoptosis, and metastasis through metabolic interconversions, including phosphorylation, glycosylation, and the generation of sphingosine-1-phosphate. This review aims to elucidate the mechanisms through which sphingolipid metabolism orchestrates cancer cell fate and drives breast cancer progression. Particular emphasis is placed on the balance between proapoptotic ceramides and pro-survival metabolites, such as sphingosine-1-phosphate, which collectively influence tumor growth and the therapeutic response. Additional sphingolipid species, including glucosylceramide and gangliosides (GD2, GD3, GM1, and GM3), have also been implicated in promoting breast cancer development. Furthermore, sphingolipid-based therapeutic strategies, including immunotherapy and antibody therapy, are discussed. By providing a comprehensive overview of sphingolipid metabolism, this review aims to identify novel therapeutic targets that may help overcome treatment resistance and improve clinical outcomes in breast cancer.

Human papillomavirus (HPV) infection is a major global health concern due to its association with various cancers, particularly cervical and head and neck squamous cell carcinomas. High-risk HPV types, such as HPV16 and HPV18, employ oncoproteins E6 and E7 to disrupt host cell regulatory pathways, promote immune evasion, and facilitate malignant transformation. Natural killer (NK) cells, critical components of innate immunity, play a pivotal role in surveilling and eliminating HPV-infected cells. However, HPV-mediated immune evasion mechanisms, including downregulation of MHC-I, suppression of chemokine signaling (e.g., CXCL14), and upregulation of inhibitory molecules (e.g., TIGIT, KLRG1), impair NK cell functionality. This review explores the intricate interactions between HPV and NK cells, highlighting the impact of HPV on NK cell infiltration, exhaustion, and receptor expression. Additionally, it discusses emerging therapeutic strategies to enhance NK cell activation, such as pharmacological agents (e.g., γ-PGA, α-GalCer), innate immune agonists (e.g., STING, RIG-I), genetic engineering (e.g., CAR-NK, iPSC-NK cells), and combination therapies with immune checkpoint inhibitors or monoclonal antibodies (e.g., cetuximab). Clinical applications, including adoptive NK cell transfer and biomarker-guided personalized immunotherapy, are also reviewed. Despite challenges like immunosuppressive tumor microenvironments and limited NK cell persistence, advancements in genetic engineering and nanoparticle delivery systems offer promising solutions. Future research should focus on integrating mechanistic insights with clinical trial design to optimize NK cell-based therapies for HPV-associated malignancies.

N6-methyladenosine (m6A) RNA methylation regulators have been implicated in colorectal cancer (CRC) progression. However, systematic evaluation using multiple machine learning approaches for prognostic prediction remains limited. This study aimed to develop and validate machine learning models for CRC prognosis based on m6A regulators and assess their potential for immunotherapy response prediction. We analyzed 1,047 CRC patients from TCGA and GEO databases (70% training, 30% validation). Twenty machine learning algorithms were systematically evaluated, with LASSO regression selecting optimal features from 27 m6A regulators. SHAP analysis provided model interpretability. Immune microenvironment characterization and immunotherapy response prediction were performed using established computational methods. LASSO regression selected eight m6A regulators (IGF2BP2, METTL3, HNRNPA2B1, METTL14, YTHDF2, VIRMA, FTO, ALKBH5) for model construction. Among 20 algorithms tested, Random Forest achieved optimal performance (training AUC = 0.895, validation AUC = 0.847). SHAP analysis identified IGF2BP2 (mean |SHAP| = 0.42) and METTL3 (mean |SHAP| = 0.36) as primary contributors to risk prediction. Risk stratification showed significant survival differences (HR = 2.41, 95% CI: 1.73-3.36, p < 0.001). Low-risk patients demonstrated enhanced immune infiltration with higher CD8⁺ T cells (17.8% vs. 10.2%, p < 0.001) and better predicted immunotherapy response rates (36.5% vs. 20.3%, p = 0.006). Our systematic machine learning analysis demonstrates that m6A regulators can effectively predict CRC prognosis and immunotherapy response. The eight-gene signature provides a practical tool for clinical risk assessment and treatment decision-making.

Cadonilimab is the first bispecific antibody independently developed in China that simultaneously targets Programmed Cell Death Protein-1 (PD-1) and Cytotoxic T Lymphocyte-Associated Antigen-4 (CTLA-4), marking a significant milestone in both clinical applications and drug development. Through its dual mechanism of action, cadonilimab blocks PD-1 and CTLA-4 signaling pathways concurrently, thereby activating T cells and enhancing antitumor immune responses. Within the tumor microenvironment, cadonilimab promotes effector T-cell infiltration while reducing nonspecific attacks on normal tissues, thus lowering the incidence of immune-related adverse events. In comparison to conventional monospecific antibodies, cadonilimab exhibits superior selectivity and safety. Multiple studies have shown that, either as monotherapy or in combination regimens, cadonilimab exhibits promising antitumor activity and tolerability in refractory solid tumors such as advanced cervical cancer, hepatocellular carcinoma, non-small cell lung cancer, and gastric cancer, with notable efficacy even in patients with low or negative PD-L1 expression. The successful development of cadonilimab not only underscores China's innovative capabilities in the field of cancer immunotherapy but also provides valuable insights for global drug development and clinical practice. However, most signals derive from phase I/II single-arm or small-sample studies with limited follow-up, and no randomized head-to-head trials have yet confirmed superiority over standard PD-1+CTLA-4 approaches. This review summarizes the mechanism of action, structural characteristics, clinical research progress, and future applications of cadonilimab, with the aim of offering a useful reference for research and clinical treatment while promoting its broader application in oncology.

Skin cutaneous melanoma (SKCM) is a highly aggressive malignancy originating from melanocytes, with a continuously rising global incidence. Developing strategies for early prevention and precise treatment remains a major challenge in oncology. Notably, advances in immunotherapy have brought new hope to SKCM patients. Increasing evidence suggests that various forms of regulated cell death, particularly cuproptosis and ferroptosis, can modulate the tumor microenvironment (TME) by inducing the death of both tumor and immune cells, thereby influencing the efficacy of immunotherapy. Consequently, there is a critical need to establish methods for early diagnosis and to develop reliable prognostic models prognostic models based on immune-related biomarkers.

We integrated RNA sequencing data and corresponding clinical information from SKCM patients obtained from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. Using single-cell transcriptomic data from the GSE72056 dataset, we analyzed the expression patterns of cuproptosis-ferroptosis-related genes (CFRGs) in SKCM and their enrichment in immune cell subsets. Key CFRG features were screened using machine learning algorithms to construct a prognostic risk-scoring model, which demonstrated robust predictive performance across multiple independent cohorts. Furthermore, we explored the associations between core CFRGs and patient survival outcomes, immunotherapy response, and drug sensitivity in SKCM.

We identified 10 key genes that were significantly associated with SKCM survival and successfully constructed a machine learning-based prognostic prediction model. This model showed strong predictive performance and demonstrated superior accuracy compared with existing prognostic models, as supported by cross-cohort and cross-cancer validation. Four key genes (IFNG, PTPN6, SLC38A1, and SOCS1) were further identified through association analyses with clinical phenotypes and showed significant correlations with clinical characteristics. Distinct immune cell infiltration patterns were observed between high- and low-risk groups stratified by these genes, indicating marked heterogeneity within the TME. This heterogeneity may directly influence patient responses to immunotherapy. Additionally, molecular docking analyses identified several potential therapeutic compounds, among which selumetinib demonstrated strong binding affinity to the target proteins IFNG, PTPN6, and SOCS1, suggesting a potential therapeutic strategy for advanced SKCM.

IFNG, PTPN6, SLC38A1, and SOCS1 may serve as potential biomarkers of poor prognosis in SKCM patients. These genes demonstrate predictive value for immunotherapy response and drug sensitivity, particularly indicating susceptibility to selumetinib treatment, and therefore show substantial potential for clinical translation.

Ramsay Hunt syndrome (RHS) typically presents with unilateral otalgia, herpes zoster oticus, ipsilateral peripheral facial palsy, and often ipsilateral vestibulocochlear involvement. Bilateral/contralateral vestibular dysfunction is extremely rare.

A 60-year-old female with a history of right breast cancer presented to our clinic with 1 week of vertigo, followed by 2 days of right-sided facial deviation and otalgia. Physical examination revealed vesicular eruptions around the right ear and external auditory canal, right-sided peripheral facial palsy, spontaneous horizontal-rotatory nystagmus (with a fast phase to the left), and postural instability. Further evaluation confirmed bilateral vestibular hypofunction: the video head impulse test showed reduced gains and/or saccades in all canals; bithermal caloric testing demonstrated bilateral vestibular weakness (sum of slow-phase velocity: 10.1°/s); and symptom assessments yielded a visual analog scale (VAS) score of 7/10 and a dizziness handicap inventory (DHI) total score of 52. Facial nerve electrophysiological testing indicated significant impairment of the right facial nerve, with an amplitude reduction exceeding 50%. The stapedial reflex, Hallpike-Dix test, Roll test, pure-tone audiometry, brain and cranial nerve MRI, and routine laboratory tests showed no significant abnormalities. A diagnosis of RHS with bilateral vestibular dysfunction was established, and treatment was administered per current guidelines, including antiviral therapy, oral corticosteroids, analgesics, anti-vertigo medications, acupuncture, and vestibular rehabilitation. After 2 weeks, symptoms (facial palsy, otalgia, herpes zoster, and dizziness) improved slightly, with crusting of the herpes lesions. At the 3-month follow-up, the herpes zoster had resolved without residual pain, though mild residual dizziness (VAS 2, DHI 20) and facial weakness persisted.

This case shows rare bilateral vestibular involvement and initial vestibular impairment preceding RHS (distinct from classical ipsilateral or rare post-RHS contralateral patterns). Elucidating the specific pathogenic mechanisms underlying this presentation holds significant clinical importance for understanding bilateral vestibular involvement.

Arising from extracranial cancers, brain metastases (BrM) are the most prevalent brain malignancy in adults. Even though there are recent advances in systemic cancer therapies and immunotherapies, the prognosis for BrM remains poor, with median survival rather dismal. The central nervous system (CNS) presents a distinct immunological and structural landscape that restricts immune surveillance and effective therapeutic delivery. This immune privilege is enforced by the blood brain barrier (BBB), specialized myeloid populations, in conjunction with reduced lymphatic drainage, which collectively constrains the effector immune cell trafficking and antigen presentation. Thus, immunotherapeutic strategies that have revolutionized systemic oncology, such as immune checkpoint inhibitors (ICIs) and chimeric antigen receptor (CAR)-T cell therapies, have presented only rather modest benefit in BrM. While immunotherapy-focused research has largely focused on T-cell-mediated mechanisms, an accumulation of recent findings suggest that B cells play multifaceted and underexplored roles within the unique CNS tumor microenvironment (TME). Aside from antibody production, B cells contribute to antigen presentation, cytokine secretion, and the formation of tertiary lymphoid structures which are functions that can either promote or suppress antitumor immunity depending on their differentiation state and local cues. In primary brain tumors, like glioblastoma (GBM), B cell infiltration has been linked to both enhance immune activation and immune regulation, yet their significance in BrM remains comparatively undefined. Understanding how B cells adapt and function within the niche constraints of the CNS, such as how they influence immune suppression, antigen presentation, and TME remodeling, may reveal new therapeutic vulnerabilities and allow for harnessing complementary B cell-based immunotherapies instead of T cell-focused approaches. This review synthesizes current knowledge on the structural and immunological features that differentiate BrM from primary brain tumors and extracranial metastases. We highlight the emerging evidence on B cell biology in the CNS, and discuss their immunostimulatory and immunoregulatory capacities, while exploring ongoing efforts to leverage B cell-based immunotherapies in brain malignancies, specifically proposed BrM. By defining the immunological landscape of BrM and the therapeutic promise of B cells, this work suggests a new possibility in CNS oncology, where humoral immunity may be harnessed to target brain metastatic malignancies.

Cancer remains a major global health challenge, and although immunotherapy has achieved remarkable breakthroughs, its efficacy is often limited by tumor-induced immunosuppression within the tumor microenvironment (TME). Emerging evidence indicates that metabolic reprogramming plays a pivotal role in shaping the TME and regulating antitumor immune responses. Targeting tumor and immune cell metabolism has therefore become a promising strategy to enhance the effectiveness of cancer immunotherapy. This review first summarizes the metabolic reprogramming that occurs within the TME, including alterations in glucose, lipid, and amino acid metabolism in tumor cells, as well as the metabolic adaptation of immune cells. We then highlight recent advances in natural products that modulate key metabolic pathways and their potential to reshape the immunosuppressive TME. Special emphasis is placed on natural compounds that not only inhibit tumor cell metabolism but also restore the metabolic fitness of immune cells, thereby improving antitumor immunity. In addition, advances in delivery strategies, including nanocarrier-based and stimuli-responsive systems, are reviewed for their roles in improving the bioavailability, stability, and tumor targeting of natural metabolism-regulating agents. Finally, we discuss the current status and challenges of translating natural metabolism-regulating agents into clinical applications, including issues of dose optimization, safety evaluation, and patient selection. Despite these hurdles, precision targeting of metabolic pathways, interdisciplinary collaboration, and the discovery of novel compounds-particularly immune-sensitizing agents derived from traditional medicine-are expected to accelerate progress. Collectively, natural products represent promising adjuvant strategies for cancer immunotherapy, with great potential to overcome current therapeutic limitations and improve clinical outcomes.

Tissue inhibitor of metalloproteinase 1 (TIMP1) plays diverse roles in extracellular matrix (ECM) remodeling, immune regulation, and tumor progression. However, its systemic patterns across cancers and cardiovascular disease remain incompletely understood.

We applied an integrative pipeline beginning with microarray analysis of tumor-bearing mouse hearts (GSE63032) to identify TIMP1 as a hub gene. Pan-cancer datasets from TCGA/GTEx and public portals were analyzed for expression, genomic alterations, epigenetic regulation, immune infiltration, prognosis, and drug sensitivity. Single-cell RNA-seq was used to define cell type-specific expression. As all large-scale analyses were performed using publicly available bioinformatics datasets, cell line experiments were used for targeted validation of TIMP1 expression and function. Findings were validated by immunohistochemistry, western blotting, and transwell assays in colorectal and gastric cancer models, with additional analysis performed in atherosclerosis cohort (GSE100927) and heart failing cohort (GSE5406) to explore cardiovascular relevance.

TIMP1 was consistently upregulated across cancers, especially in colorectal and gastric tumors, where it correlated with adverse survival and high diagnostic accuracy. Genomic analyses revealed copy number alterations, while promoter hypomethylation aligned with increased expression in digestive cancers. Drug-response profiling indicated sensitivity to epigenetic inhibitors and resistance to MAPK-targeted agents. Single-cell analyses localized TIMP1 to myeloid cells in colorectal cancer and fibroblasts in gastric cancer, linking it to apoptosis, EMT, angiogenesis, and stromal-immune crosstalk. Beyond oncology, TIMP1 was elevated in atherosclerosis, aligning with immune- and lipid-related pathways, but reduced in heart failure, where it was linked to impaired mitochondrial metabolism.

This multi-level and bioinformatics study identifies TIMP1 as a cross-disease regulator with context-dependent functions. TIMP1 serves as a potential prognostic and diagnostic biomarker in digestive cancers, a therapeutic stratification marker for epigenetic interventions, and a candidate mediator linking tumor biology with cardiovascular disorders such as atherosclerosis and heart failure.

Ovarian cancer (OC), particularly epithelial ovarian cancer (EOC), represents one of the most lethal and aggressive gynecological malignancies. Despite advances in surgery, chemotherapy, and immunotherapy, patient survival remains poor. Identifying novel molecular targets is crucial for improving early diagnosis and developing more effective therapies.

We examined the expression and immunoregulatory function of SLC40A1 in EOC using both experiments on cells and mouse orthotopic tumor models. Through integrated in vitro and in vivo studies, we systematically assessed the role of SLC40A1 in promoting M1 macrophage polarization and its relationship with tumor suppression, demonstrating that SLC40A1 enhances the response to immunotherapy.

SLC40A1 was found to be more highly expressed in normal ovarian tissues compared with EOC tissues, and its high expression was associated with a favorable prognosis. In vitro, SLC40A1 did not significantly affect tumor cell proliferation, apoptosis, or migration and invasion. However, in vivo experiments using mice with differing immune status demonstrated that SLC40A1 modulates the tumor immune microenvironment. Subsequent bioinformatics analyses suggested that SLC40A1 may regulate M1 macrophage polarization. Mechanistically, in vitro experiments confirmed that SLC40A1 regulates CXCL11 secretion, which activates the JAK2-STAT1 signaling pathway, promoting macrophage TNF-α production, which in turn upregulates SLC40A1 expression. Finally, we demonstrated that SLC40A1 enhances the response to immunotherapy.

These findings identify SLC40A1 as a key regulator of the antitumor immune response in EOC. High SLC40A1 expression is associated with enhanced macrophage-mediated tumor suppression and improved response to immunotherapy, highlighting its potential as both a prognostic biomarker and a therapeutic target.