Latest ArticlesOsimertinib (OSI) therapy, a cornerstone in treating non-small cell lung cancer (NSCLC), has been severely limited by rapidly developing acquired resistance. Inhibition of bypass activation using a combination strategy holds promise in overcoming this resistance. Biguanides, with excellent anti-tumor effects, have recently attracted much attention for this potential. The current study investigated whether novel biguanide compounds developed by our team could overcome OSI resistance and the underlying mechanisms were explored.
A comprehensive screening assay using OSI-resistant cells identified the optimal combination of biguanide compounds with OSI. Proteomics, co-immunoprecipitation mass spectrometry, RNA sequencing, and homologous recombination assays were used to elucidate the molecular mechanisms underlying combination therapy. NSCLC tumor tissues, especially OSI-resistant tissues, obtained from our clinic were used to assess the correlations between key proteins and OSI resistance.
SMK-010, a highly potent biguanide compound, effectively overcame OSI resistance in vitro and in vivo. Mechanistical studies showed that BMI1/FGFR1 pathway activation is responsible for OSI resistance. Specifically, silencing BMI1 promoted NEDD4-mediated FGFR1 ubiquitination and proteasomal degradation, whereas SMK-010 treatment induced FGFR1 lysosomal degradation. This reduction in FGFR1 levels impaired homologous recombination, increased DNA damage, and surmounted OSI resistance. Analysis of clinical samples revealed overexpression of BMI1 and FGFR1 in NSCLC tissues and represented potential biomarkers for OSI resistance.
These findings highlight the crucial role of the BMI1/FGFR1 axis in OSI resistance and provide a rational basis for the future clinical application of the biguanide, SMK-010, in combination with OSI.
Current clinical staging of pancreatic ductal adenocarcinoma (PDAC) relies predominantly on anatomical resectability, thus limiting its prognostic utility. We developed and validated a pretreatment prognostic grading system incorporating multidimensional parameters.
Patients with histologically confirmed PDAC undergoing curative-intent pancreatectomy were retrospectively enrolled. Independent prognostic determinants of overall survival (OS) and disease-free survival (DFS), identified through multivariable Cox proportional hazards regression, provided the basis for deriving the Tianjin Prognostic Score and its corresponding risk stratification scheme.
Resectability status, lymph node metastasis indicated by imaging, pretreatment serum CA19-9 levels, and the prognostic nutritional score (PNS) independently predicted both OS and DFS. These parameters were integrated into the Tianjin Prognostic Score for PDAC prognosis stratification. The Tianjin-Grade system, subsequently established according to this score, segregated patients into 4 discrete prognostic cohorts with significantly divergent survival outcomes. This system exhibited significantly greater discriminatory ability for prognosis than conventional serum CA19-9 and resectability criteria. Notably, patients classified as having high risk or extremely high risk derived substantial survival benefits from neoadjuvant chemotherapy (NAC), whereas those with low or intermediate risk demonstrated comparable survival outcomes regardless of NAC administration.
The Tianjin-Grade system provides accurate pretreatment prognosis prediction in patients with PDAC through integration of anatomical and biological parameters, thus serving as a reliable tool for prognostic assessment. This system facilitates the development of personalized preoperative therapeutic strategies.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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