Cancer Biology & Medicine最新文献

Objective: Tumor-associated macrophages (TAMs) exhibit heterogeneous properties including anti-tumorigenic and pro-tumorigenic phenotypes. The rate-limiting enzyme in de novo serine biosynthesis, 3-phosphoglycerate dehydrogenase (PHGDH), has a well-established role in cellular metabolism, yet its specific role in macrophages remains unknown.

Methods: Metabolomics assays were conducted to assess metabolite composition and dynamics in macrophages. Changes in polarization and immunosuppressive markers were validated with qRT-PCR. Bioinformatics was used to analyze immune cell subsets and associated metabolic pathways. Finally, ChIP-qPCR and co-immunoprecipitation assays were performed to elucidate the downstream regulatory mechanisms of PHGDH.

Results: Serine metabolism was found to be downregulated in TAMs in breast cancer. Functional studies revealed that PHGDH inhibition promotes an M2-like phenotype and immunosuppressive functions in macrophages. Furthermore, PHGDH was found to undergo nuclear translocation during macrophage polarization. Mechanistically, nuclear PHGDH was found to regulate GLUD1 and GLS2 transcription via interaction with the transcription factor STAT3. Rescue experiments demonstrated that glutamine supplementation and STAT3 inhibition reversed the effects of PHGDH on macrophage function.

Conclusions: Our findings reveal a previously unrecognized non-canonical metabolic function of PHGDH, thus providing potential therapeutic targets in the tumor microenvironment for reversing malignant progression.

Senescent macrophages have emerged as dynamic cells within the tumor microenvironment that significantly promote tumor progression through complex cellular and molecular functional alterations. This review explores the multifaceted roles of macrophage senescence in cancer, and establishes links between senescent macrophages and tumor progression from multiple perspectives, on the basis of the first comprehensive analysis of the molecular mechanisms and pathways involved. By systematically examining the diverse changes in senescent macrophages, this review integrates and analyzes their effects on tumors, thus offering a comprehensive and novel theoretical foundation, and practical insights for cancer treatment. Notably, by integrating current molecular research and therapeutic advancements, we summarize novel therapeutic strategies targeting senescent macrophages, including senolytics, senescence modulators, and cutting-edge immunotherapies, thereby highlighting the potential of senescent macrophages as a therapeutic target and introducing new opportunities for cancer treatment.

The management of breast cancer, one of the most common and heterogeneous malignancies, has transformed with the advent of precision medicine. This review explores current developments in genetic profiling, molecular diagnostics, and targeted therapies that have revolutionized breast cancer treatment. Key innovations, such as cyclin-dependent kinases 4/6 (CDK4/6) inhibitors, antibody-drug conjugates (ADCs), and immune checkpoint inhibitors (ICIs), have improved outcomes for hormone receptor-positive (HR+), HER2-positive (HER2+), and triple-negative breast cancer (TNBC) subtypes remarkably. Additionally, emerging treatments, such as PI3K inhibitors, poly (ADP-ribose) polymerase (PARP) inhibitors, and mRNA-based therapies, offer new avenues for targeting specific genetic mutations and improving treatment response, particularly in difficult-to-treat breast cancer subtypes. The integration of liquid biopsy technologies provides a non-invasive approach for real-time monitoring of tumor evolution and treatment response, thus enabling dynamic adjustments to therapy. Molecular imaging and artificial intelligence (AI) are increasingly crucial in enhancing diagnostic precision, personalizing treatment plans, and predicting therapeutic outcomes. As precision medicine continues to evolve, it has the potential to significantly improve survival rates, decrease recurrence, and enhance quality of life for patients with breast cancer. By combining cutting-edge diagnostics, personalized therapies, and emerging treatments, precision medicine can transform breast cancer care by offering more effective, individualized, and less invasive treatment options.

Objective: Although the role of circular RNAs (circRNAs) in tumor progression and immune regulation is well-known, the specific circRNA molecules that mediate immune responses after radiotherapy (RT) and the underlying mechanisms have not been identified.

Methods: Cytometry with time-of-flight (CyTOF) was used to analyze blood samples from patients with liver cancer exhibiting abscopal effects (AEs) after stereotactic body radiotherapy (SBRT) to quantify the number of dendritic cells (DCs) and CD8⁺ T cells and interferon-beta (IFN-β) level. circTMEM56 and IFN-β levels were measured in 76 patients with liver cancer using qPCR and ELISA. Immunohistochemistry validated circTMEM56 and CD141 staining in tissues. The interaction between circTMEM56, miR-136-5p, and STING, as well as the impact on anti-tumor immunity, was verified using circTMEM56-specific probes, dual-luciferase activity assays, proteomics analysis, and western blot analysis.

Results: The role of circTMEM56 in enhancing anti-tumor immunity and response to RT in hepatocellular carcinoma (HCC) was determined. Higher circTMEM56 levels were linked to an improved RT response and better clinical outcomes in patients with HCC. circTMEM56 enhanced cGAS-STING signaling, increased the number of tumor-infiltrating CD8⁺ T cells, and elevated the serum IFN-β levels. Moreover, circTMEM56 administration significantly boosted the response to RT in tumors with low circTMEM56 expression.

Conclusions: High circTMEM56 expression in HCC modulates the distant effects of HCC RT by activating the cGAS-STING pathway to reshape the tumor microenvironment. This study provides a new approach to improve RT efficacy for HCC.

Objective: Based on multistage metabolomic profiling and Mendelian randomization analyses, the current study identified plasma metabolites that predicted the risk of developing gastric cancer (GC) and determined whether key metabolite levels modified the GC primary prevention effects.

Methods: Plasma metabolites associated with GC risk were identified through a case-control study. Bi-directional two-sample Mendelian randomization analyses were performed to determine potential causal relationships utilizing the Shandong Intervention Trial (SIT), a nested case-control study of the Mass Intervention Trial in Linqu, Shandong province (MITS), China, the UK Biobank, and the FinnGen project.

Results: A higher genetic risk score for plasma L-aspartic acid was significantly associated with an increased GC risk in the northern Chinese population (SIT: HR = 1.26 per 1 SD change, 95% CI: 1.07-1.49; MITS: HR = 1.07, 95% CI: 1.00-1.14) and an increased gastric adenocarcinoma risk in FinnGen (OR = 1.68, 95% CI: 1.16-2.45). Genetically predicted plasma L-aspartic acid levels also modified the GC primary prevention effects with the beneficial effect of Helicobacter pylori eradication notably observed among individuals within the top quartile of L-aspartic acid level (P-interaction = 0.098) and the beneficial effect of garlic supplementation only for those within the lowest quartile of L-aspartic acid level (P-interaction = 0.02).

Conclusions: Elevated plasma L-aspartic acid levels significantly increased the risk of developing GC and modified the effects of GC primary prevention. Further studies from other populations are warranted to validate the modification effect of plasma L-aspartic acid levels on GC prevention and to elucidate the underlying mechanisms.