Cancer Biology & Medicine最新文献

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.

Chimeric antigen receptor-T (CAR-T) cell therapy is a precise immunotherapy for lymphoma. However, its long-term efficacy faces many challenges related to tumor cell heterogeneity, interference from immunosuppressive microenvironments, CAR-T cell exhaustion, and unmanageable adverse events. Diverse modifications have been introduced into conventional CAR-T cells to overcome these obstacles; examples include addition of recognition sites to prevent immune escape, coupling of cytokine domains to enhance killing ability, blocking of immune checkpoint signals to resist tumor microenvironments, and inclusion of suicide systems or safety switches to improve safety and flexibility. With increasing understanding of the importance of metabolism and epigenetics in cancer and cytotherapy, glycolysis, methylation, and acetylation have become crucial CAR-T cell therapeutic targets. Universal and in situ CAR-T cells are also expected to be used in clinical applications, thus providing hope to patients with relapsed/refractory lymphomas.

Objective: The high heterogeneity of hepatocellular carcinoma (HCC) renders traditional therapies unable to effectively activate the patient's immune system to combat tumors. Patients with advanced HCC and T cell functional deficiencies may benefit more from cellular immunotherapy, especially tumor neoepitope-targeted T cell receptor (TCR)-T cells. Neoepitopes with strong immunogenicity provide precise targets for HCC, further enhancing the efficacy of cellular immunotherapy.

Methods: A scalable workflow for identifying neoepitopes from 7 HLA-A*02:01-restricted patients with HCC was established based on whole exome sequencing and bioinformatics analyses, followed by identification of neoepitope-specific TCRs through tetramer-based screening and single-cell TCR cloning technology, which were further validated in the JC4 cell model. The cytotoxicity of CD8⁺ TCR-T cells was evaluated in neoepitope-positive tumor cell lines or NCG mice.

Results: Ten specific neoepitopes were identified, among which neoepitope B and T lymphocyte attenuator^P267L [BTLA^P267L (SLNHSVIGL)] exhibited advantageous properties as a potential tumor target. Three TCRs (85-3, 126-5, and 52-3) were confirmed to specifically recognize the neoepitope BTLA^P267L, while no cross-recognition of irrelevant or wild-type epitopes was observed. Activated BTLA^P267L-specific CD8⁺ TCR-T cells released extensive perforin, granzyme B, IFN-γ, and TNF-α in vitro, thereby inducing strong cytotoxic effects against BTLA^P267L-positive T2 or HCC cell lines. BTLA^P267L-specific CD8⁺ TCR-T cells mediated robust tumor regression due to long-lasting survival and released perforin without causing significant cytotoxic effects on normal organs in murine experiments.

Conclusions: This preclinical study demonstrated the beneficial effects of neoepitope BTLA^P267L-specific TCR-T cell immunotherapy, unlocking a novel strategy for personalized precision therapy in HCC.

Alterations in the mesenchymal-epithelial transition factor (MET) gene are critical drivers of non-small cell lung cancer (NSCLC). In recent years advances in precision therapies targeting MET alterations have significantly expanded treatment options for NSCLC patients. These alterations include MET exon 14 skipping mutations (MET exon 14 skipping), MET gene amplifications, MET point mutations (primarily kinase domain mutations), and MET protein overexpression. Accurate identification of these alterations and appropriate selection of patient populations and targeted therapies are essential for improving clinical outcomes. The East China Lung Cancer Group, Youth Committee (ECLUNG YOUNG, Yangtze River Delta Lung Cancer Cooperation Group) has synthesized insights from China's innovative drug development landscape and clinical practice to formulate an expert consensus on the diagnosis and treatment of NSCLC patients with MET alterations. This consensus addresses key areas, such as optimal testing timing, testing methods, testing strategies, quality control measures, and treatment approaches. By offering standardized recommendations, this guidance aims to streamline diagnostic and therapeutic processes and enhance clinical decision-making for NSCLC with MET alterations.

Objective: Identifying biomarkers that predict the efficacy and prognosis of chemoradiotherapy is important for individualized clinical treatment. We previously reported that high murine double minute 1 (MDM1) expression in patients with rectal cancer is linked to a favorable chemoradiation response. In this study the role of MDM1 in the chemoradiotherapy response in colorectal cancer (CRC) patients was evaluated.

Methods: Colony formation and cell proliferation assays as well as xenograft models were used to determine if MDM1 expression affects the sensitivity of CRC cells to chemoradiation. RNA sequencing revealed that MDM1 regulates tumor protein 53 (TP53) expression and apoptosis. A series of molecular biology experiments were performed to determine how MDM1 affects p53 expression. The effects of inhibitors targeting apoptosis on MDM1 knockout cells were evaluated.

Results: Gene expression profiling revealed that MDM1 is a potential chemoradiotherapy sensitivity marker. The sensitivity of CRC cells to chemoradiation treatment decreased after MDM1 knockout and increased after MDM1 overexpression. MDM1 affected p53 expression, thereby regulating apoptosis. MDM1 overexpression limited YBX1 binding to TP53 promoter, regulated TP53 expression, and rendered CRC cells more sensitive to chemoradiation. In CRC cells with low MDM1 expression, a combination of apoptosis-inducing inhibitors and chemoradiation treatment restored sensitivity to cancer therapy.

Conclusions: The current study showed that MDM1 expression influences the sensitivity of CRC cells to chemoradiation by influencing p53 and apoptosis pathways, which is the basis for the underlying molecular mechanism, and serves as a possible predictive marker for chemoradiotherapy prognosis.

As the leading cause of cancer-related deaths, lung cancer remains a noteworthy threat to human health. Although immunotherapies, such as immune checkpoint inhibitors (ICIs), have significantly increased the efficacy of lung cancer treatment, a significant percentage of patients are not sensitive to immunotherapies and patients who initially respond to treatment can quickly develop acquired drug resistance. Bispecific antibodies (bsAbs) bind two different antigens or epitopes simultaneously and have been shown to enhance antitumor efficacy with suitable safety profiles, thus attracting increasing attention as novel antitumor therapies. At present, in addition to the approved bsAb, amivantamab, three novel bsAbs (KN046, AK112, and SHR-1701) are being evaluated in phase 3 clinical trials and many bsAbs are being evaluated in phase 1/2 clinical trials for patients with non-small cell lung cancer (NSCLC). Herein we present the structure, classification, and mechanism of action underlying bsAbs in NSCLC and introduce related clinical trials. Finally, we discuss challenges, potential solutions, and future prospects in the context of cancer treatment with bsAbs.

Objective: Suppression of tumorigenicity 2 (ST2), the receptor for interleukin (IL)-33, has a critical role in tumor growth, angiogenesis, metastasis, and immune modulation. The IL-33/ST2 pathway is known to influence the polarization and function of macrophages, which is integral to modulating the tumor microenvironment. However, the precise role of IL-33/ST2 in tumors, particularly non-small cell lung cancer (NSCLC), has not been established.

Methods: ST2 expression in NSCLC was analysed using a murine model and patient specimens. The effect of the IL-33/ST2 axis on macrophage polarization in NSCLC was determined.

Results: Elevated ST2 expression was correlated with aggressive tumor growth. Specifically, ST2 expression on macrophages was associated with lung cancer progression and the absence of ST2 on macrophages was associated with diminished tumor growth. IL-33 promoted polarization of alternatively activated macrophages in an ST2-dependent manner that was mediated via the PI3K/Akt signalling pathway. Moreover, IL-33 inhibited T-cell function by inducing the secretion of transforming growth factor β from alternatively activated macrophages.

Conclusions: Macrophages expressing ST2 can serve as promising therapeutic targets for NSCLC immunotherapy, highlighting the IL-33/ST2 axis as a potential target for future antitumor strategies.