The transforming growth factor-β (TGF-β) family consists of evolutionarily conserved cytokines that regulate various physiological processes across nearly all tissue and cell types. While TGF-β signaling plays a critical role in immune homeostasis and tissue repair, its dysregulation is implicated in multiple diseases, particularly cancer. Given its dual role in tumor suppression and promotion, TGF-β has emerged as a promising yet challenging therapeutic target. Preclinical studies have demonstrated significant tumor inhibition through TGF-β signaling blockade using diverse classes of inhibitors. However, despite extensive research and clinical trials spanning over two decades, no TGF-β inhibitors have been approved for cancer therapy, underscoring a significant disconnect between preclinical promise and clinical efficacy. This review systematically examines the tumorigenic mechanisms driven by TGF-β and evaluates the therapeutic landscape of anti-TGF-β inhibitors, including receptor kinase inhibitors, neutralizing antibodies, bifunctional ligand traps, integrin-mediated TGF-β therapy, antisense oligonucleotides, TGF-β-targeted vaccines, and various combination strategies. By comparing preclinical and clinical findings, we highlight key challenges and propose novel approaches to improve the translational success of TGF-β-targeted therapies. These insights provide a foundation for optimizing future research and advancing the clinical application of TGF-β inhibitors in oncology.

Cellular senescence, a state of irreversible cell cycle arrest accompanied by a senescence-associated secretory phenotype (SASP), plays dual roles in cancer biology. Initially recognized as a tumor-suppressive mechanism by halting the proliferation of damaged cells, senescence paradoxically fosters tumor progression through SASP-mediated immunosuppression and chronic inflammation. Thus, the role of senescent cells in tumors still needs to be further elucidated. Our review comprehensively examines the triggers and molecular pathways of senescence. We also summarized the characteristics and functions of senescent tumor and nontumor cells, delineating the heterogeneous tumor senescence microenvironment. Here, we highlight the functional reprogramming of senescent cells, including enhanced stemness, secretome and metabolome reprogramming, which can sustain tumorigenesis and therapeutic resistance. Furthermore, we discuss emerging therapeutic strategies, notably the “one-two punch” approach to overcome therapy resistance. By integrating recent advances in senescence-targeted therapies, our review underscores the necessity of context-specific strategies to harness senescence's tumor-suppressive effects while mitigating its protumorigenic consequences. These insights provide a roadmap for developing precision therapies and refining biomarker-driven approaches to improve cancer treatment outcomes.

Immune checkpoints, the key gatekeepers of immune homeostasis, have become the central targets of modern cancer immunotherapy. These regulatory pathways, composed of co-suppressive and co-stimulatory molecules, enable the immune system to distinguish between self and non-self while preventing excessive tissue damage. However, tumor cells strategically block these protective mechanisms through aberrant expression of checkpoint ligands, creating an immunosuppressive microenvironment that promotes tumor immune evasion and metastatic progression. Yet, immune checkpoint therapy is not universally applied due to its specific mechanisms. This review systematically describes the immune checkpoints that function on various types of immune cells, as well as their molecular structure and functional diversity, and elucidates their role in achieving tumor immune escape. We analyze the clinical translation of immune checkpoint inhibitors (ICIs) and their combination therapies. In addition, we combine preclinical findings with clinical trial data to provide a comprehensive framework for understanding the mechanisms of action and clinical applications of immune checkpoints, as well as to present the challenges in terms of immune-related adverse events of ICIs. This review provides a valuable perspective for developing next-generation immunotherapies and optimizing personalized treatment strategies.

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.

Tumor microenvironment-responsive imaging-guided therapy has emerged as a novel approach for malignant tumor prognosis and therapy. A multifunctional nanoscale drug delivery system is often employed to realize diagnosis, treatment, monitoring, and evaluation by combining a therapeutic unit and an imaging unit to enable. In this study, we designed and prepared a theranostic nanomedicine by conjugating a small-molecular gadolinium chelate (Diethylenetriaminepentaacetic acid Gadolinium[III] chelate, Gd-DOTA) and a chemotherapeutic drug paclitaxel (PTX) via a cathepsin B-responsive linker (glycylphenylalanylleucylglycine, Gly-Phe-Leu-Gly, GFLG) onto a peptide dendron-hyaluronic acid (HA) hybrid. Upon reaching the tumor microenvironment, the GFLG linker was cleaved by overexpressed cathepsin B, leading to simultaneous release of PTX for targeted chemotherapy and Gd-DOTA for enhanced magnetic resonance imaging (MRI). The experiments demonstrated that the theranostic nanomedicine significantly enhanced MRI contrast and exhibited superior antitumor efficacy in 4T1 breast tumor models without pronounced systemic toxicity. Importantly, under the tumor microenvironment, effective release and clearance of Gd-DOTA from the hybrid postimaging reduced the risk of long-term toxicity. This study presents a feasible approach for cancer theranostics by integrating precise imaging, targeted therapy, and rapid clearance of toxic drugs in a single platform. This promising nanomedicine could be explored for clinical translation.

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.

Ferroptosis is a form of iron-dependent regulated necrosis characterized by the abnormal accumulation of peroxidized phospholipids containing polyunsaturated fatty acids (PUFA-PLs). The conversion of PUFA to PUFA-CoA is critical for the synthesis of PUFA-PLs and is reliant on ATP, yet the role of mitochondrial ATP production in regulating ferroptosis remains unclear. In this study, we employed a metabolite deprivation and replenishment system coupled with flow cytometry to investigate the interplay between glutamine metabolism, mitochondrial ATP, and ferroptosis. We demonstrated that depriving cells of glutamine increases intracellular levels of reactive oxygen species (ROS), while also unexpectedly inhibiting ferroptosis induced by cystine deprivation. Mechanistically, glutamine deficiency impaired mitochondrial ATP production, and pharmacological inhibition of mitochondrial ATP export to the cytosol effectively blocked ferroptosis. Further analysis revealed that mitochondrial ATP depletion under glutamine-deficient conditions hindered the conversion of PUFAs to PUFA-CoA, thereby limiting PUFA-PL synthesis and ferroptosis execution. Notably, although glutamine deprivation alone did not directly trigger ferroptosis, it promoted PUFA oxidation and prostaglandin-endoperoxide synthase 2 (PTGS2) expression via ROS accumulation. Together, our findings highlight the critical role of mitochondrial ATP in ferroptosis regulation and provide new insights into the metabolic control of cell death pathways.

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.

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.