2026年 · 第04卷第02期

The mevalonate pathway plays a crucial role in the metabolic reprogramming of pancreatic ductal adenocarcinoma (PDAC), driving lipid biosynthesis, redox homeostasis, and oncogenic signaling, thereby sustaining tumor progression and therapeutic resistance. Its integration with Kirsten rat sarcoma viral oncogene homolog (KRAS)-driven signaling networks establishes it as a cornerstone of PDAC biology and a promising therapeutic target. The products of the pathway (sterols and isoprenoids) support key processes such as membrane biogenesis, protein prenylation, and immune evasion, facilitating tumor adaptation to the harsh microenvironment. Despite extensive research, therapeutic resistance and metabolic plasticity present considerable challenges in targeting this pathway. This review synthesizes current knowledge regarding the biochemical regulation of the mevalonate pathway in PDAC, its crosstalk with key oncogenic signaling networks, and emerging therapeutic strategies. In addition, we highlight critical knowledge gaps, including the complex regulatory crosstalk of the pathway with oncogenes, tumor suppressors, and nutrient-sensing pathways, and the mechanisms by which metabolic rewiring modulates tumor–immune interactions and therapy resistance. By integrating insights from pre-clinical and clinical studies, we highlight promising novel combination therapies, including statins, bisphosphonates, and sterol regulatory element-binding protein (SREBP) inhibitors, as well as the potential for precision medicine approaches targeting mevalonate pathway vulnerabilities. Addressing these challenges may provide new avenues for improving therapeutic outcomes in PDAC.

Methionine restriction (MR) has shown significant promise in cancer therapy because it targets the unique methionine dependency of many tumors. However, despite extensive research on MR, a clear synthesis of preclinical findings and their translation into clinical settings is lacking. This review aims to address this gap by consolidating existing evidence, identifying challenges, and highlighting opportunities for advancing MR as a viable cancer treatment strategy. Preclinical studies have revealed that MR effectively hinders cancer cell proliferation, triggers cell cycle arrest, and enhances the effectiveness of standard treatments, including chemotherapy and radiotherapy. Mechanistically, MR disrupts critical cancer pathways by influencing epigenetic regulation, redox balance, and autophagy. Moreover, animal models have demonstrated notable tumor suppression and extended survival, underscoring the therapeutic potential of MR. Early-phase clinical trials are now examining MR in combination with established therapies, reporting positive preliminary results regarding safety and tolerability, and investigating biomarkers for predicting patient responsiveness. These findings suggest the utility of MR as a complementary treatment strategy, particularly for tumors resistant to conventional therapies. The outcomes of this study underscore the importance of further research to refine MR protocols, understand long-term effects, and identify optimal patient groups. Furthermore, combining MR with immunotherapies, targeted treatments, and advanced modalities such as chimeric antigen receptor (CAR)-T cell therapy may offer new therapeutic pathways. Additionally, the development of MR-mimetic drugs and targeted supplements can improve patient compliance and broaden the therapeutic applicability of MR. Large-scale clinical trials are essential to evaluate the efficacy of MR across diverse cancer types, focusing on sustainability and safety over extended periods. If successful, MR can transform cancer therapy by exploiting metabolic vulnerabilities in cancer cells, providing a novel and less toxic treatment option for challenging malignancies.

Cancer is the second leading cause of death globally, claiming >10 million lives in 2020 and a projected increase to 13 million by 2030. Traditional treatments such as chemotherapy, radiation, and surgery can be effective but often lead to systemic toxicity and drug resistance due to their lack of selectivity. Nanotechnology is a promising alternative that targets cancer cells and reduces harm to healthy tissues. This review provides a comprehensive synthesis of current advances in nanotechnology-based delivery systems for arthropod venom–derived peptides, highlighting their therapeutic potential, mechanistic advantages, and translational challenges in cancer treatment. Nanoparticles (NPs) ranging from 1 to 100 nm improve drug delivery and treatment outcomes by enhancing bioavailability, controlling drug release, and exploiting tumor-specific features. However, challenges including poor in vivo biocompatibility, complex large-scale manufacturing, and stringent regulatory requirements have hindered their widespread clinical translation. Arthropod venom contains bioactive compounds that primarily target ion channels, which play a role in cancer progression. Venom-derived peptides are emerging as promising anticancer agents, and nanotechnology offers an effective strategy for their delivery. NPs have enhanced therapeutic potential by improving controlled release, stability, and cellular uptake while minimizing toxicity. Liposomal- and lipid-based NPs and organic carriers such as chitosan show particular promise for targeted drug delivery. Combining nanotechnology with venom-derived peptides, particularly those from arthropods such as scorpions, may enhance the selectivity and efficacy of cancer treatments. These peptides selectively target cancer cells, minimize toxicity, and improve therapeutic outcomes. This review highlights the potential of venom-derived peptides combined with NPs in cancer therapy, along with their benefits, challenges, and future research directions toward innovative therapeutic strategies. Future studies should focus on optimizing venom peptide formulations with NPs to enhance efficacy, reduce systemic toxicity, and develop safer and more effective cancer treatments.

Despite significant advances in cancer diagnosis and therapy, the global burden of cancer continues to escalate, characterized by increasing incidence and mortality rates. A problem for successful treatment is chemoresistance, which undermines the effectiveness of traditional and targeted treatments. This review synthesizes emerging therapeutic strategies, including targeted agents, combinatorial regimens, and advances in precision medicine, with a focus on improving clinical outcomes. Integrating the latest understanding from molecular biology, genomics, and pharmacology emphasizes new paths to overcoming resistance. This review critically examines the contributions of exosomes, metabolic reprogramming, and the tumor microenvironment to chemoresistance, and highlights emerging therapeutic strategies aimed at restoring drug sensitivity.

Background: Resting tumor-associated macrophages (TAMs) are stimulated by the tumor microenvironment and can be primarily polarized into two subtypes: M1-and M2-like. M1-like TAMs promote inflammation and eradicate tumor cells, whereas M2-like TAMs suppress inflammation and facilitate tumor development. However, the mechanisms underlying phenotypic switching in these macrophages remain unclear. Therefore, we aimed to characterize the gene expression profiles of M1-like and M2-like TAMs in pan cancers. Methods: Three computational methods were used to estimate the infiltration score of TAMs in 9239 tumor samples across 31 solid cancer types, based on RNA sequencing databases. Tumor samples were divided into high- and low-score groups based on the median M1/M2 ratio. Furthermore, gene enrichment, protein interactions, and transcription factors were analyzed. Multiple pharmaco–omics profiles were used to identify potential drugs. Finally, binding between the compounds and drug targets was validated using molecular docking. Results: Among the top 100 dysregulated genes in each cancer type, 70 and 82 downregulated genes were consistently differentially expressed across most cancer types. We identified candidate drugs targeting protein phosphatase 2A (PP2A), a core protein. These included efaproxiral, hesperidin, ezetimibe, calcitriol, and linopirdine. Conclusions: This study provides a pan-cancer characterization of the TAM polarization-related gene profile. Network pharmacology and molecular docking analyses revealed five promising therapeutic agents for TAM reprogramming. Thus, our findings provide valuable insights into the enhancement of immune responses to inhibit tumor immune escape and metastasis.

Background: Anti-thymocyte globulin (ATG) is widely used in allogeneic hematopoietic stem cell transplantation (allo-HCT) to prevent severe graft-versus-host disease (GVHD) and graft failure. Insufficient ATG exposure may reduce its effectiveness in GVHD prophylaxis, while excessive exposure can elevate the risk of viral reactivation, non-relapse mortality (NRM), and disease relapse. Based on monitoring ATG (Thymoglobulin, Sanofi, Lyon, France) concentrations, we developed an ATG-targeted dosing strategy and conducted a prospective, single-arm study on patients undergoing unrelated donor peripheral blood stem cell transplantation (URD-PBSCT) to evaluate its efficacy and safety. Methods: We enrolled 30 patients with malignant hematological diseases who underwent URD-PBSCT between January 2020 and June 2023. All patients received an ATG-targeted dosing strategy, involving a 4-day administration of ATG: 1.5 mg/kg on day -5, 2.5 mg/kg on day -4, with dose adjustments on day -3 and day -2 to achieve an optimal area under the concentration–time curve (AUC) for active ATG. Engraftment, viral infections, acute and chronic GVHD, relapse, and survival outcomes were statistically analyzed. A historical cohort of 38 patients who underwent URD-PBSCT between December 2014 and December 2020 was used for comparison. Patients in the historical cohort received a fixed total dose of 10 mg/kg ATG from day -5 to day -2. Results: All patients in the targeted dosing cohort achieved successful neutrophil and platelet engraftment with 100% donor chimerism. The cumulative incidence of cytomegalovirus (CMV) reactivation and persistent CMV viremia at 180 days post-transplantation was 30.0% and 16.7%, respectively. The cumulative incidences of Epstein–Barr virus (EBV) reactivation and persistent EBV viremia at 180 days were 46.7% and 23.3%, respectively. The cumulative incidences of grades II–IV and III–IV acute GVHD at 100 days were 49.4% and 9.3%, respectively. The 1-year cumulative incidence of relapse (CIR) was 10.0%, the 1-year NRM was 10.0% (95% CI: 2.5% -23.6%), the 1-year disease-free survival (DFS) was 80.0% (95% CI: 60.8% -90.5%), and the 1-year overall survival (OS) was 86.7% (95% CI: 68.3% -94.8%). Compared with the historical cohort, the targeted dosing cohort showed significantly lower cumulative incidences of CMV reactivation (30.0% vs. 78.9%, P < 0.001) and persistent CMV viremia (16.7% vs. 42.1%, P = 0.026) on day 180. However, no significant differences were observed in EBV reactivation (46.7% vs. 68.4%, P = 0.170) or persistent EBV viremia (23.3% vs. 44.7%, P = 0.075) on day 180. Similarly, there were no statistically significant differences in the cumulative incidences of grade II–IV (49.4% vs. 50.3%, P = 0.700) or grade III–IV (9.3% vs. 18.8%, P = 0.390) acute GVHD on day 100, or 1-year chronic GVHD (10.0% vs. 13.2%, P = 0.680). Conclusions: Utilizing a targeted ATG dosing strategy in URD-PBSCT was associated with a lower incidence of CMV reactivation and viremia without increasing the risk of acute or chronic GVHD.

Primary cardiac tumors are rare and often present diagnostic challenges due to their non-specific symptoms and imaging characteristics. In this report, we present a case of right atrial intimal sarcoma (IS) with liver metastasis. A 49-year-old woman presented to the emergency department with acute dyspnea, cyanosis, nausea, vomiting, and upper abdominal pain. Echocardiography revealed a large pericardial effusion and a mass in the right atrium. Contrast-enhanced computed tomography (CT) and positron emission tomography/CT (PET/CT) confirmed the presence of multiple nodules in the right atrium and hepatic masses, suggesting metastatic disease. Laboratory tests indicated liver dysfunction, with elevated carbohydrate antigen 125 (CA125) and normal alpha-fetoprotein (AFP) levels. These clinical features initially suggested a diagnosis of hepatocellular carcinoma with isolated cardiac metastasis. However, the final pathological examination and gene sequencing results were unexpected, leading to the diagnosis of right atrial IS with liver metastasis. The patient was managed conservatively and remained alive for 8 months at the time of manuscript submission.