MedComm – Oncology最新文献

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.

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.

Gastric cancer, the fifth most common cancer worldwide, is particularly heavy in China, accounting for 39.5% of global deaths, reported by the International Agency for Research on Cancer (IARC). While timely evaluation of long-term survival of gastric cancer is crucial for guiding early detection screening programs, data on long-term relative survival (RS) for gastric cancer are scarce in China. Traditional methods for estimating 5-year RS require complete 5-year follow-up data, leading to delays of at least 5 years for survival estimates—a challenge that similarly affects 10-, 15-, and 20-year RS. The period analysis approach, introduced by Brenner, overcomes this limitation by enabling more current survival estimates without requiring complete follow-up data [1]. This method is considered the “gold standard” for assessing cancer survival using data from population-based registry and is widely applied in Western countries. In the current study, we aimed to provide, using period analysis, the most recent serial data on long-term survival for gastric cancer patients from a Chinese population, including 5-, 10-, 15-, and 20-year RS.

Our data came from four high-quality cancer registries in Taizhou City, ranked fifth in population size in Zhejiang Province, China. These registries were selected based on the criterion that death certificate-only (DCO) cases should account for less than 13%, as recommended by Brenner [1], which there were nine registries included initially, to ensure data reliability. Aligned with the International Classification of Diseases (ICD), flowchart of gastric cancer patients included in the analyses was shown in Figure 1A. Eventually, we include the following cases for further analyses, that is, 12,270 cases during 2004–2023 for 20-year RS, 10,515 cases (2009–2023) for 15-year RS, 7427 cases (2014–2023) for 10-year RS, and 3534 cases (2019–2023) for 5-year RS. Period analysis was used to estimate age-adjusted 5-, 10-, 15-, and 20-year RS, stratified by gender, region, and age at diagnosis. RS for patients was calculated as the ratio of observed survival divided by the expected survival based on the life tables using the Ederer II method. All survival estimates were age-adjusted RS using world population standardization for age weights. More details on data analyses are provided in the Supplementary Information S1.

The basic characteristics of gastric cancer patients were shown in Figure 1B. Approximately 69.0% of patients were males for all four intervals. Furthermore, the majority of cases stood in ≥ 45 years group (approximately 96%), and patients ≥ 65 years accounted for more than half of all gastric patients during all four intervals. As shown in Figure 1C, the most up-to-date estimates of serial data on long-term survival for gastric cancer patients from Taizhou, eastern China, reaching 58.59% for 5-year RS during 2019–2023, 53.04% for 10-years (2014–2023), 46.93% for 15-year RS

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.

Phosphatases are increasingly recognized as critical regulators of cancer biology, with important roles in both tumor cells and the tumor immune microenvironment (TIME). These enzymes modulate intracellular signaling pathways that control tumor growth, immune evasion, and metastasis. Although phosphatases were once considered undruggable, recent advances have highlighted their therapeutic potential. Despite growing evidence, phosphatases remain underexplored as drug targets, with no approved therapies to date. This review presents an in-depth overview of phosphatase classification based on catalytic domain similarities and explores their diverse functions as tumor suppressors, oncogenic drivers, or context-dependent regulators. We describe how phosphatases such as PTPN6, PTPN22, and DUSPs regulate key pathways like RAS/MAPK and PI3K/AKT in both tumor and immune cells. Additionally, we discuss the role of phosphatases in shaping the tumor microenvironment through exosome secretion. This review highlights current therapeutic strategies, including small molecules and antibodies, and their synergistic effects with kinase inhibitors and immune checkpoint blockade. By summarizing recent advances, this paper underscores the need for deeper mechanistic insights into phosphatase function in cancer and immunity. Understanding these mechanisms will be key to unlocking their potential as novel therapeutic targets in oncology.

Cancer remains a significant global health burden, ranking as the second leading cause of death despite considerable medical advances. Increasing evidence links cholesterol metabolism, particularly low-density lipoprotein cholesterol (LDL-C), to cancer risk. Epidemiological studies suggest that elevated LDL-C levels are associated with multiple cancers, including breast, colorectal, and pancreatic cancers [1]. These observations suggest that LDL-C-lowering therapies may have anticancer effects. Although preclinical studies show that statins can inhibit tumor growth and metastasis, the effects of different lipid-lowering agents on cancer risk remain unclear. To investigate this, we conducted a Mendelian randomization (MR) study leveraging genetically proxied LDL-C-lowering drug targets, including HMG-CoA reductase (HMGCR), proprotein convertase subtilisin/kexin type 9 (PCSK9), and Niemann-Pick C1-like 1 (NPC1L1) inhibitors. We examined the associations between these drug targets and 16 different cancer types, as well as overall cancer risk (Figure 1A).

Figure 1B presented the outcomes of MR analyses investigating the causal effects of genetically proxied lipid-lowering drug targets on 17 different types of cancer, alongside pleiotropy assessments. Funnel plots were used to evaluate heterogeneity. A rigorous instrument selection process yielded between 3 and 60 single nucleotide polymorphisms (SNPs) per target, with all F-statistics > 10, mitigating the risk of weak instrument bias. As for the PCSK9 inhibition (PCSK9i), the fixed-effect inverse-variance weighted (IVW) method clearly demonstrated a protective effect on breast cancer (OR: 0.9124, p = 0.0071, 95%CI: 0.8455–0.9792), which this result was corroborated by the weighted median and the weighted mode method. In addition, it also identified PCSK9i had an obvious protective effect on thyroid cancer (OR: 0.3272, p = 0.0397, 95%CI: 0.0370–0.5915) and brain cancer (OR: 0.9985, p = 1.8786E-07, 95%CI: 0.9980–0.9991), only in the IVW method. More importantly, the PCSK9i retained a strong protective association with overall cancer (OR: 0.9883, p = 5.8596E-11, 95%CI: 0.9848–0.9918). However, PCSK9i showed significant associations with higher risk of oesophageal cancer (OR: 1.0009, p = 0.0028, 95%CI: 1.0003–1.0014) and lung cancer (OR: 1.0328, p = 0.0020, 95%CI: 1.0054–1.2782). Additionally, genetically predicted HMGCR inhibition (HMGCRi) had a positive correlation effect on the risk of breast cancer (OR: 0.8266, p = 0.0001, 95%CI: 0.7300–0.9232), ER+ breast cancer (OR: 0.8281, p = 0.0013, 95%CI: 0.7130–0.9431), serous ovarian cancer (OR: 0.7564, p = 0.0213, 95%CI: 0.5187–0.9941), overall ovarian cancer (OR: 0.5954, p = 2.25081E-05, 95%CI: 0.3555–0.8352), kidney cancer (OR: 0.9883, p = 5.85958E-11, 95% CI: 0.9848–0.9918), brain cancer (OR: 0.9982, p = 0.0168, 95%CI: 0.9967–0.9997) and overall ca

Mitochondria, as the main site for aerobic respiration in cells, are indispensable participants in the reprogrammed metabolic activities of tumor cells. Mitochondrial ribosomal proteins (MRPs), essential components of the mitochondrial ribosome (mitoribosome), play a critical role in maintaining mitochondrial function and regulating oncogenic signaling. Their molecular mechanisms and biological functions make MRPs key regulators of tumorigenesis, drug resistance, and tumor immune escape. MRPs are abnormally expressed in various cancer types and are linked to the prognosis of cancer patients. However, a thorough grasp of the specific mechanisms and a holistic analysis of the relationship between MRPs and different cancers are lacking. This review highlights the specific regulatory roles of MRPs, including MRPS5, MRPS29, MRPL9, MRPL12, MRPL13, MRPL33, MRPL58, and MRPL59, in cancer. Additionally, we examine the potential of MRPs as prospective clinical biomarkers and discuss their relationship with clinical prognosis and treatment response. We further explore the underlying reasons for the diverse functions of MRPs, their implications in cellular signaling and tumor immunity, and consider the prospects for developing MRP inhibitors as therapeutic strategies. Our comprehensive analysis deepens the understanding of MRPs complex biological functions and emphasizes their promising potential as therapeutic targets in cancer treatment.