Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively triggers cancer cell death via its association with death receptors on the cell membrane, but exerts negligible side effects on normal cells. However, some non-small-cell lung carcinoma (NSCLC) patients exhibited resistance to TRAIL treatment in clinical trials, and the mechanism varies. In this study, we described for the first time that toosendanin (TSN), a triterpenoid derivative used in Chinese medicine for pain management, could significantly sensitize human primary NSCLC cells or NSCLC cell lines to TRAIL-mediated apoptosis both in vitro and in vivo, while showing low toxicity against human primary cells or tissues. The underlying apoptotic mechanisms involved upregulation of death receptor 5 (DR5) and CCAAT/enhancer binding protein homologous protein, which is related to the endoplasmic reticulum stress response, and is further associated with reactive oxygen species generation and Ca²⁺ accumulation. Surprisingly, TSN also induced autophagy in NSCLC cells, which recruited membrane DR5, and subsequently antagonized the apoptosis-sensitizing effect of TSN. Taken together, TSN can be used to sensitize tumors and the combination of TRAIL and TSN may represent a useful strategy for NSCLC therapy; moreover, autophagy serves as an important drug resistance mechanism for TSN.

Dysregulated endocrine hormones (EHs) contribute to tumorigenesis, but how EHs affect the tumor immune microenvironment (TIM) and the immunotherapy of non–small cell lung cancer (NSCLC) is still unclear. Here, endogenous ouabain (EO), an adrenergic hormone, is elevated in patients with NSCLC and closely related to tumor pathological stage, metastasis, and survival. EO promotes the suppression of TIM in vivo by modulating the expression of immune checkpoint proteins, in which programmed cell death protein ligand 1 (PD-L1) plays a major role. EO increases PD-L1 transcription; however, the EO receptor Na- and K-dependent adenosine triphosphatase (Na, K-ATPase) α1 interacts with PD-L1 to trigger the endocytic degradation of PD-L1. This seemingly contradictory result led us to discover the mechanism whereby EO cooperates with Na, K-ATPase α1 to finely control PD-L1 expression and dampen tumoral immunity. In conclusion, the Na, K-ATPase α1/EO signaling facilitates immune escape in lung cancer, and manipulation of this signaling shows great promise in improving immunotherapy for lung adenocarcinoma.

Immunotherapy is becoming a powerful approach in the treatment of breast cancer. However, high response rates in the majority of breast cancer patients have yet to be achieved.

A more accurate prognosis is important for clinical treatment of lung adenocarcinoma. However, due to the limitation of sample and technical bias, most prognostic signatures lacked reproducibility, and few were applied to clinical practice. In addition, understanding the molecular driving mechanism is indispensable for developing more promising therapies for lung adenocarcinoma. Here, we built an unbiased prognostic significance model to perform an integrative analysis, including differentially expressed genes and clinical data with lung adenocarcinoma patients from TCGA. Multivariable Cox proportional hazards model with the Lasso penalty and 10-fold cross-validate were used to identify the best gene signature. We generated a 17-gene signature for prognostic risk prediction based on the overall survival time of lung adenocarcinoma patients. To further test the model’s predictive ability, we have applied an independent GEO database to verify the predictive ability of prognostic signature. The model can more objectively describe several biological processes related to tumors and reveal important molecular mechanisms in tumor development by GO and KEGG analysis. Furthermore, differential expression analysis by GSEA revealed that tumor microenvironments such as ER stress, exosome, and immune microenvironment were enriched. Using single-cell RNA sequence technology, we found that risk score was positively correlated with lung adenocarcinoma marker genes and copy number variation but negatively correlated with lung epithelial marker genes. High-risk cell populations with the model had stronger cancer stemness and tumor-related pathway activation. As we expected, the risk score was in accordance with the malignancy of each cluster from tumor progression. In conclusion, the risking model established in this study is more reliable than others in evaluating the prognosis of LUAD patients.

Background: Sirtuin 3 (SIRT3) is a key mitochondrial regulator that functions as an oncogene in breast cancer, where its overexpression drives chemoresistance. Targeting SIRT3 offers a strategy to overcome resistance mechanisms and improve chemotherapy efficacy. Methods: We utilized molecular docking-based virtual screening to identify SIRT3 inhibitors from a natural product library. Candidates were validated via molecular dynamics simulations and binding assays. Efficacy was tested in breast cancer cells and an orthotopic mouse model by assessing cell viability, apoptosis, mitochondrial function, and tumor growth during cisplatin treatment. Results: Jionoside B1 was identified as a potent SIRT3 inhibitor that suppresses enzymatic activity, leading to increased SOD2 acetylation. In breast cancer cells, Jionoside B1 significantly enhanced cisplatin sensitivity by promoting ROS accumulation, disrupting mitochondrial potential, and triggering apoptosis. In vivo, the combination of Jionoside B1 and cisplatin inhibited tumor growth more effectively than cisplatin alone. Conclusions: Jionoside B1 sensitizes breast cancer cells to cisplatin by inhibiting SIRT3-mediated oxidative stress defense. These findings highlight Jionoside B1 as a promising therapeutic candidate for combination chemotherapy to enhance cisplatin responsiveness in breast cancer.