Hao Wu

Dietary lignans sensitize triple-negative breast cancer to paclitaxel through gut-microbiota-derived N , N -dimethylsphingosine, which suppresses PDGFRA/PI3K–AKT signaling.

The extracellular matrix (ECM) forms a dynamic structure around cells, providing environmental cues, mechanical support, and tissue protection. It is composed of fibrous proteins, glycosaminoglycans (GAGs), proteoglycans, and glycoproteins. The molecular, physical, and mechanical properties of the ECM regulate the motility, survival, and function of immune cells. In most cancers, inflammatory cytokines and proteases—particularly matrix metalloproteinases(MMPs)—released within the immune-infiltrated inflammatory microenvironment can remodel the ECM. Cytokines such as tumor necrosis factor-α (TNF), interleukin, and transforming growth factor-beta (TGF-β) modulate the expression of various ECM molecules and promote host cell differentiation, thereby shaping a stroma conducive to tumor survival and metastasis. When ECM components become dysregulated, they act as ligands interacting with immune cell receptors, suppressing the function of specific immune cell subsets in the tumor microenvironment (TME), and activating downstream intracellular signaling pathways that are exploited by cancer cells to facilitate progression. This review systematically outlines key ECM constituents, molecular mediators of ECM remodeling, and their role in regulating immune cell behavior, including T cell exhaustion and macrophage polarization. It also elucidates the direct interactions between ECM and immune cells within inflammatory settings. Furthermore, we explore therapeutic strategies targeting ECM-mediated immunosuppression in solid tumors. This study highlights promising approaches to enhance the efficacy of cancer immunotherapy.

Background: N-acetyltransferase 10 (NAT10) mediated N4-acetylcytidine (ac4C) modification has been implicated in tumor progression; however, the precise role and underlying mechanism of NAT10 in breast cancer progression remain largely undefined. Methods: The expression and prognostic significance of NAT10 in breast cancer were evaluated using clinical tissue samples and public databases. Functional assays were performed in vitro and in vivo to assess the effects of NAT10 on tumor growth and immune evasion. Mechanistic studies, including RNA immunoprecipitation (RIP), ac4C RNA immunoprecipitation (acRIP), and co-immunoprecipitation (Co-IP), were conducted to elucidate the interaction between NAT10 and histone deacetylase 4 (HDAC4) and their roles in regulating NF-κB signaling and programmed death-ligand 1 (PD-L1) expression. Results: NAT10 expression was significantly upregulated in breast cancer and correlated with poor patient prognosis. NAT10 mediated ac4C modification enhanced the stability of HDAC4 mRNA, thereby promoting HDAC4 expression. Conversely, HDAC4 stabilized NAT10 protein through post-transcriptional deacetylation, forming a self-reinforcing regulatory loop. Elevated HDAC4 activated the NF-κB signaling pathway, resulting in increased PD-L1 transcription and enhanced immune evasion of breast cancer cells. Inhibition of the NAT10/HDAC4/NF-κB axis markedly reduced PD-L1 expression and restored antitumor immune responses. Conclusion: Our findings identify a self-reinforcing NAT10/HDAC4 signaling circuit that drives breast cancer progression and immune evasion. Targeting NAT10 represents a promising therapeutic strategy to overcome immunosuppression and improve patient outcomes in breast cancer.

The molecular heterogeneity and distinct features of HER2‐low breast cancer are poorly understood, limiting their precise management. To address this issue, longitudinal multiomic profiling of HER2‐low breast cancer is performed, including genomics, transcriptomics, proteomics, lactylomics, and phosphoproteomics, using 250 well‐characterized samples, and identified three proteomic subtypes: PS1 (estrogen response signaling enriched), PS2 (angiogenesis enriched), and PS3 (proliferation enriched and HER2‐high like). These three proteomic subtypes have distinct features and potential therapeutic strategies, namely, endocrine therapy, antiangiogenic therapy, and anti‐HER2 therapy, and are validated in external datasets and PDO models. In addition, a detailed description of the genomic characteristics and a map of the lactate modification landscape of HER2‐low breast cancer are provided. This research provides complementary information, reveals the molecular characteristics of HER2‐low breast cancer, and suggests potential precise therapeutic strategies for patients with this type of cancer.

Metabolic reprogramming and epigenetic modification are two hallmarks of cancer. Protein lysine lactylation (Kla) is a novel type of glycolysis lactate-triggered posttranslational modification. However, the role of Kla in breast cancer (BC) remains largely unknown. Here, western blot, and immunohistochemical (IHC) staining of BC tissues revealed that global Kla levels were upregulated in BC tissues, and high levels of Kla were correlated with poor prognosis of patients with BC. A series of in vitro and in vivo assays demonstrated that interruption of glycolysis by lactate dehydrogenase (LDH) inhibitor or silencing LDHA and LDHB repressed the malignant behaviors of BC cells. Moreover, 4D label-free quantitative lactylproteomics analysis of BC tissues and cells revealed that lactylated proteins widely existed in several subcellular compartments and were closely associated with various cancer-related biological processes. Notably, two previously unresearched sites of histone lactylation, H4K79 lactylation (H4K79la) and H4K91 lactylation (H4K91la), were identified to be hyperlactylated in cancer tissues and cells. Glycolytic genes, such as lactate dehydrogenase A (LDHA), phosphoglycerate kinase 1 (PGK1), and hexokinase 1 (HK1) were identified to be the potential candidate genes epigenetically regulated by H4K79la and H4K91la by intersecting through chromatin immunoprecipitation sequencing (ChIP-seq), RNA sequencing (RNA-seq), and TCGA-BRCA database. Pharmacological inhibition of glycolysis downregulated H4K79 and H4K91 lactylation and suppressed the expression of glycolytic genes, whereas treatment with sodium lactate exhibited the opposite effects. Additionally, E1A-binding protein p300 (P300) acted as lysine lactyltransferase to regulate H4K79la and H4K91la, and control the transcription and expression of downstream glycolytic genes in BC cells. The results revealed an intriguing positive feedback loop formed by glycolysis/H4K79la/H4K91la/glycolytic genes in BC, highlighting the relationship between metabolic reprogramming and epigenetic regulation. These findings provide new therapeutic targets for patients with BC.

Colorectal cancer (CRC) remains a significant oncological challenge, being among the foremost contributors to cancer-related mortality worldwide. This review summarizes our current knowledge regarding how metabolic reprogramming, specifically the Warburg effect, contributes to CRC pathobiology and explores its therapeutic relevance. Metabolic reprogramming in CRC is characterized by a shift from oxidative phosphorylation to glycolysis, termed the Warburg effect. Driven by the tumor microenvironment (TME), this adaptation enhances cancer cell proliferation through accelerated ATP generation, biosynthesis support, and redox balance. Key glycolytic enzymes, namely hexokinase, phosphofructokinase, pyruvate kinase, and lactate dehydrogenase are now prioritized as therapeutic targets in CRC treatment strategies. Diagnostic modalities utilizing CRC’s altered metabolism such as 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET/CT) and metabolomic analysis of circulating metabolites, improved early detection through enhanced sensitivity and specificity. These approaches reveal CRC’s distinct metabolic signatures, enabling precise disease stratification and management. Therapeutic strategies targeting the EMP pathway show preclinical efficacy in overcoming CRC-associated chemoresistance and radioresistance. Modulation of EMP-regulating pathways (AKT, AMPK, mTOR) provides additional therapeutic opportunities. However, CRC’s metabolic heterogeneity demands multi-targeted approaches. The development of targeted therapies must consider the potential off-target effects on normal tissues that rely on EMP, necessitating a careful balance between therapeutic efficacy and safety. In summary, this review underscores the complexity of metabolic reprogramming in CRC and the need for a nuanced approach to target these pathways effectively. Subsequent investigations should prioritize defining tumor-selective metabolic vulnerabilities and engineering multi-pathway interventions that spare normal tissues, ultimately advancing therapeutic precision in CRC management.

Ankyrin repeat domain 52 (ANKRD52) is a regulatory component of the protein phosphatase 6 (PP6) holoenzyme. Evidence has emerged to suggest involvement of ANKRD52 in tumor metastases and cancer cell escape from T cell-mediated elimination and immunotherapy but there has been no research across different cancer types. The current study explored the biological functions of ANKRD52 by combining data from many databases. The aim was to expose new diagnostic or treatment biomarkers for malignant tumors. The roles of ANKRD52 with respect to immunotherapy in 33 human cancer types were analyzed by combining data from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), Cancer Cell Line Encyclopedia (CCLE), UCSC Xena, the Tumor Immune Estimation Resource (TIMER), TISIDB and Cellminer. Bioinformatics methods were used to analyze the association between ANKRD52 expression and prognosis, immunological indicators (immune cell infiltration, ESTIMATE scores and tumor microenvironment (TME) signatures), tumor mutational burden (TMB), microsatellite instability (MSI) and drug sensitivity. ANKRD52 expression was generally higher in 24 tumor tissues than in normal tissues and was associated with poor prognosis, especially in kidney chromophobe (KICH). Lower expression was observed in advanced cancer. ANKRD52 expression was strongly linked to major immunological indicators, such as immune cell infiltration, ESTIMATE scores, TME signatures, as well as expression of immune and tumor-related genes. Expression was also associated with indicators of immunotherapy efficacy and outcome, such as TMB in 7 cancer types and MSI in 12. In addition, ANKRD52 expression was linked to sensitivity to a number of anticancer drugs. ANKRD52 had a distinct immune function in breast invasive carcinoma (BRCA) that correlated negatively with most immune indicators. Expression was enriched in proliferation-, differentiation- and metabolism-related pathways and linked to other immune cells and TME signatures. A nomogram to predict 3- or 5-year overall survival (OS) of patients with BRCA was constructed. ANKRD52 may have utility as an oncological and immunological biomarker. New insights into oncogenesis are presented and the development of ANKRD52-targeting to increase the therapeutic efficacy of immunotherapy combined with chemotherapy explored.

Background Complement C1q binding protein (C1QBP) is upregulated in breast cancer (BRCA) and is involved in cell growth, immunity, and apoptosis. This study explores the potential relationship of C1QBP with the development, prognosis, and immune response of BRCA. Methods All original data were downloaded from the The Cancer Genome Atlas (TCGA) database. C1QBP expression was analyzed in normal and cancerous tissues by gepia2. The CIBERSORT algorithm evaluated the relationship between C1QBP expression and immune infiltration through the TCGA dataset. To analyze the mechanisms of C1QBP in BRCA, Gene Set Enrichment Analysis (GSEA), Gene Set Variation Analysis (GSVA), and weighted gene co-expression network (WGCNA) package were used. The analyses of the relevance of C1QBP to cancer drug sensitivity were performed by using the GDSC database. Results The expression of C1QBP in BRCA tissues was significantly upregulated and high C1QBP expression in BRCA patients was associated with poor prognosis. The co-expression between C1QBP and immune-related genes such as CXCL16 as well as tumor regulatory genes, such as DGUOK and FXN, existed in BRCA. C1QBP was related to the infiltration of regulatory T cells and other immune cells in BRCA. High expression of C1QBP negatively affected the drug sensitivity of commonly used chemotherapeutic drugs. Finally, we presented a nomogram model that can predict BRCA prognosis. Conclusion C1QBP affects the development, immune infiltration, drug treatment effect and prognosis of BRCA through various pathways and may become the potential prognostic and immunologic biomarkers and therapeutic targets for BRCA.