MedComm – Oncology最新文献

There is a complex pathological association between neurodegenerative diseases and cancer. The epidemiological negative correlation between Parkinson's disease (PD) and brain tumor is particularly noteworthy. PD is characterized by the loss of dopaminergic neurons and the formation of Lewy bodies, while glioma, the representative of brain tumors, originates from the malignant transformation of glial cells. The molecular interaction network between these two diseases is elusive, limiting the development of cross-disease treatment strategies. This review systematically summarizes the associations between PD and glioma in genetic predispositions, epigenetic modifications, alterations in subcellular compartments, and cellular mechanisms concerning neurons, glial cells, and stem cells. Additional links arise from circadian rhythm regulation, oxidative stress, and gut microbiota, underscoring the importance of systemic pathways that connect neurodegeneration and tumorigenesis. Within this context, cancer neuroscience emerges as a critical framework, demonstrating how neuronal activity drives cancer progression by shaping the tumor microenvironment. Therapeutic opportunities build upon these mechanistic insights, including engineering neuron types to suppress cancer growth, modulating synaptic genes, inducing neuronal cell death cascades, and controlling inflammation to disrupt tumor-nerve crosstalk. Emerging neuroscience-inspired technologies may drastically expand the treatment landscape. This review tries to unveil a potential theoretical paradigm for developing precise therapies with both neuroprotection and antitumor effects.

Breast cancer brain metastasis (BCBrM) remains a major clinical challenge with limited therapeutic options and poor prognosis. Despite advances in systemic therapy, the incidence of BCBrM is rising due to prolonged survival of patients with advanced breast cancer, yet effective brain-targeted strategies remain scarce, underscoring a critical research gap. This review integrates recent mechanistic insights that illuminate the complex biology underpinning BCBrM and explores how these discoveries are driving therapeutic innovation. We detail the metastatic cascade from local invasion to brain colonization, and examine key signaling pathways orchestrating brain-specific metastasis. Emphasis is placed on the dynamic crosstalk between tumor cells and the brain microenvironment, including astrocytes, microglia, and neurons, as well as metabolic reprogramming and immune evasion. We critically evaluate current preclinical models and their translational relevance, highlighting recent advances in humanized and imaging-based systems. Emerging therapies, such as central nervous system-penetrant kinase inhibitors, antibody–drug conjugates, and immunotherapies, are discussed alongside persistent challenges in drug delivery and resistance. Finally, we outline future directions, calling for cross-disciplinary collaboration and innovative clinical trial designs to personalize care and improve patient outcomes. Together, this review underscores the urgent need to bridge biology and therapy to transform the management of BCBrM.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major risk factor for hepatocellular carcinoma (HCC), yet treatment options for advanced disease remain limited. O-GlcNAc transferase (OGT), the enzyme catalyzing O-GlcNAcylation, has been implicated in tumorigenesis, but its pro-cancer mechanism in MASLD-HCC remains poorly defined. Here, we show that OGT expression is significantly upregulated during MASLD-HCC progression and negatively regulates the tumor suppressor phosphatase and tensin homolog deleted on chromosome ten (PTEN) both in vivo and in vitro. Mechanistically, OGT catalyzes O-GlcNAcylation of PTEN at T382, which competitively inhibits the phosphorylation at the same residue. This modification promotes PTEN ubiquitination and accelerates its degradation. Importantly, O-GlcNAcylation of PTEN simultaneously impairs its intrinsic phospholipase activity. These dual effects compromise PTEN function, leading to activation of PI3K/Akt signaling pathway and enhanced tumor cell proliferation and migration. Moreover, pharmacological inhibition of OGT suppresses tumor growth and, when combined with PI3K/Akt pathway inhibitors, produces additive antitumor effects. These findings reveal a novel mechanism by which OGT-mediated O-GlcNAcylation destabilizes and inactivates PTEN, driving MASLD-HCC progression. They also highlight OGT and PTEN as promising therapeutic targets for developing novel strategies against HCC.

Aging is a complex biological process that significantly influences human health, including susceptibility to cancer. Although aging and cancer are distinct phenomena, they intersect through shared molecular mechanisms such as genomic instability, telomere attrition, epigenetic alterations, and chronic inflammation. Despite increasing recognition of these connections, how aging-related changes influence cancer development and treatment remains poorly understood. This review explores the intricate relationship between aging and cancer, highlighting how age-related changes in the tumor microenvironment, systemic inflammation and cellular senescence contribute to oncogenesis and tumor progression. We also assess the impact of aging on cancer treatment outcomes, as well as how cancer and its therapies may contribute to the acceleration of biological aging. Furthermore, we discuss potential intervention strategies that target the aging-related mechanisms that drive cancer development and progression. We review current progress and future directions in aging and cancer research, emphasizing that, with continuous technological advances and deepening insights, incorporating aging biology into oncology is both timely and necessary. By integrating recent advances in cancer biology and geroscience, this review offers insights critical for designing age-adapted therapeutic strategies. It underscores the need to shift toward personalized oncology approaches that account for the biological and clinical heterogeneity of aging.

The DEAD-box RNA helicase 17 (DDX17) is strongly linked to the occurrence and development of specific human cancers, emphasizing its previously unrecognized biological roles in cancer progression and metastasis. However, the precise mechanisms by which DDX17 regulates liver cancer metastasis have not been thoroughly explored. In this study, increased DDX17 expression levels showed a robust association with the invasive potential of hepatocellular carcinoma (HCC) cells. Silencing DDX17 expression resulted in substantial reduction of HCC cell migration and invasion potentials, while DDX17 overexpression had the opposite effect. Silencing DDX17 also attenuated epithelial–mesenchymal transition (EMT) in HCC cells and significantly reduced metastatic lesions in an orthotopic HCC nude mouse model. Mechanistically, chromatin immunoprecipitation assays revealed that TCF4 physically interacts with the DDX17 promoter, activating its transcriptional expression. Immunoprecipitation results demonstrated that DDX17-mediated nuclear input of β-catenin is dependent on its helicase functional domain. Furthermore, we demonstrated that β-catenin/TCF4 is essential for DDX17-induced migration and invasion in HCC cells. Taken together, these findings emphasize the significance of DDX17 in the malignant progression and metastasis of HCC, revealing a novel mechanism involving the β-catenin/TCF4/DDX17 pathway.

Epstein–Barr virus-associated gastric cancer (EBVaGC) is a unique subtype of gastric cancer (GC) with distinct molecular characteristics that generally has a better prognosis. BamHI-A leftward frame 4 (BALF4), an envelope glycoprotein encoded by the Epstein-Barr virus (EBV), plays an important role in EBV infection. However, its biological function and potential molecular mechanisms in EBVaGC remain unclear. This study aimed to investigate the impact of the highly expressed viral gene BALF4 on the progression of EBVaGC. Here, we detected the expression of BALF4 in GC tissue chips and validated that the presence of BALF4 might be associated with a favorable prognosis in EBVaGC. The results showed that BALF4 inhibited the proliferation, migration, and invasion of GC cells in vitro and in vivo. In addition, we discovered that BALF4 interacts with N-acetyltransferase 10 (NAT10). High expression of NAT10 in GC tissues promotes the malignant phenotype of GC cells. We discovered that BALF4 could inhibit the malignant progression of GC by promoting the ubiquitination and degradation of NAT10. In summary, our study revealed a possible mechanism explaining the favorable prognosis of the EBVaGC subtype, which contributes to a better understanding of this special type of GC.

A groundbreaking study published in Cell Metabolism reveals how lactate promotes cancer stemness and therapy resistance by reshaping epigenetic landscapes [1]. By employing advanced single-cell tracking and machine learning in tumor organoids, the authors demonstrate that lactate suppresses differentiation and induces dedifferentiation of cancer cells into stem-like states through MYC activation. This discovery underscores lactate as a key regulator of tumor dynamics and identifies bromodomain protein 4 (BRD4) inhibitors as a promising therapeutic strategy to prevent relapse.

Tumor cells typically rely on glycolysis (the Warburg effect) for rapid energy supply, producing a large amount of lactate. Traditionally viewed as a metabolic byproduct, lactate is now recognized as a signaling molecule with multiple roles in the tumor microenvironment. The accumulation of lactate is closely associated with tumor proliferation, invasion, and drug resistance [2]. In gastric cancer, lactate promotes NBS1 K388 lactylation, enhancing MRN complex formation and recruitment to DNA double-strand breaks, thereby improving homologous recombination repair and mediating chemoradiotherapy resistance [3]. Lactate metabolism has thus emerged as a key focus in cancer research.

Cancer recurrence and metastasis remain major clinical challenges, driven largely by cancer stem cells (CSCs). CSCs exhibit self-renewal, multi-directional differentiation, and drug resistance, enabling survival post-therapy and tumor regeneration. Cancer differentiated cells (CDCs), as an important component of the tumor cell population, exhibit significant functional differences from CSCs. Research by the Rodríguez Colman team at the University Medical Center Utrecht revealed that murine intestinal stem cells and differentiated cells display distinct metabolic profiles and interact via lactate [4]. This suggests similar metabolic heterogeneity may exist between CSCs and CDCs in human intestinal tumors, with lactate playing a potential role in tumor progression. Further investigation into lactate's functional impact in these interactions is warranted.

Immunostaining of clinical samples showed that the expression level of monocarboxylate transporter 4 (MCT4), a lactate transporter, was significantly higher in CDCs than in CSCs. This indicates that CDCs have a higher glycolysis level. This finding demonstrates that, although tumor metabolism is generally characterized by the Warburg effect, there are notable differences in aerobic glycolysis levels among different tumor cell populations. Single-cell analysis further confirmed that the lactate level was elevated in CDCs relative to CSCs, indicating a higher glycolytic rate in CDCs. However, no significant differences were observed in basal glucose levels or glucose uptake between CDCs and CSCs. Interestingly, CSCs exhibited a greater capacity for lactate uptake compared to

In a recent paper published in 2025 Nature Communications, Pierini et al. [1] demonstrated that chimeric antigen receptor macrophages (CAR-M) enhance the efficacy of programmed cell death protein 1 (PD-1) immune checkpoint blockade in HER2⁺ solid tumors. Using a syngeneic HER2⁺ mouse model, the study revealed that CAR-M therapy successfully reprograms the immunosuppressive tumor microenvironment (TME), promotes infiltration of CD8⁺ cytotoxic T cells (CTLs), natural killer (NK) cells, and promotes durable antigen spreading. Notably, CAR-M therapy provided protection against antigen-negative tumor relapses, a significant clinical challenge associated with current CAR-T therapies. These findings support the potential of CAR-M as a transformative adjunct to current immunotherapy strategies.

Immune checkpoint inhibitors (ICIs) targeting PD-1 or programmed death ligand 1 (PD-L1) have revolutionized cancer immunotherapy, especially in melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma. However, their limited efficacy in solid tumors is due to multiple resistance mechanisms, including a suppressive TME dominated by tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), poor antigen presentation, and inadequate T-cell infiltration. While CAR-T therapies have demonstrated remarkable success in hematological malignancies, their limited effectiveness in solid tumors remains suboptimal. These limitations underscore the urgent need for new approaches capable of overcoming immunosuppression and enhancing antigen presentation within the TME [2].

To overcome these challenges, CAR-M therapy represents a novel and promising immunotherapeutic modality. Macrophages are naturally equipped to infiltrate tumors, phagocytose cancer cells, and cross-present tumor antigens to the adaptive immune system [3]. By engineering macrophages to express a CAR targeting a tumor-associated antigen (e.g., HER2), researchers aim to redirect these cells toward tumor destruction while harnessing their innate antigen-presenting capacity. Unlike CAR-T cells, CAR-Ms are not MHC-restricted and can engage tumors through both direct cytotoxicity and activation of other immune components. This dual functionality gives CAR-M therapy a unique advantage, convert immunologically “cold” tumors into “hot,” immune-active sites.

In the HER2⁺ mouse model, Pierini et al., administered intratumoral injections of anti-HER2 CAR-M and observed a marked increase in the infiltration of CD8⁺ T cells, CD4⁺ helper T cells, NK cells, and dendritic cells (DCs) [1]. CAR-M treatment also reprogrammed endogenous macrophages from a M2-like, pro-tumor phenotype to an M1-like, pro-inflammatory state. Importantly, this intervention led to robust antigen spreading, a phenomenon in which T cells begin to recognize and respond to tumor antigen

Metabolic reprogramming of cancer-associated fibroblasts (CAFs) plays an important role in colorectal cancer (CRC) progression. However, the mechanisms by which dysfunctional amino acid metabolism in CAFs contributes to cancer progression remain unclear. Here, we investigated amino acid metabolism in fibroblasts derived from human CRC tissues and the molecular interactions of this regulation with CRC progression. We revealed that amino acid metabolism, especially de novo glycine synthesis, was significantly activated in CAFs compared with normal fibroblasts in CRC tissues. Mechanistically, transforming growth factor β1 (TGF-β1) secreted by CRC cells was identified as a key factor that induced the activation of glycine synthesis and collagen production in CAFs. The inhibition of phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in de novo glycine synthesis, attenuated TGF-β1-induced collagen production in CAFs. Additionally, we found that collagen levels were significantly elevated in human CRC tissues. Collectively, these findings reveal a novel mechanism by which CRC cells enhance collagen production in CAFs through TGF-β1-induced de novo glycine synthesis. Our data not only highlight the pivotal role of de novo glycine synthesis in CRC progression but also provide a potential strategy for CRC treatment by targeting PHGDH.

Glycoprotein non-metastatic melanoma protein B (GPNMB) is a highly conserved transmembrane glycoprotein, which is widely involved in biological processes of tissues, cells, metabolism and immunity, regulates various signaling pathways, and plays an important role in the occurrence and development of diseases. However, the effect of GPNMB on the same biological process varies greatly in different tissues, and its application as a tumor therapeutic target is also a challenge. At the same time, how to balance the multiple effects of GPNMB is also a key issue facing future clinical applications. This paper reviews the role of GPNMB in tissue repair, metabolic regulation, cell aging, immune response, and the mechanism of GPNMB's involvement in the occurrence and development of various diseases, including tumor. In this paper, we summarize the GPNMB signaling pathway, analyze its potential value as diagnostic markers and therapeutic targets, and discuss the future research direction. Through systematic summary, this review provides a theoretical basis for further understanding of the biological function of GPNMB and its role in diseases, and also provides a new idea for the formulation of GPNMB based precision treatment strategy.