bims-meluca 2025-05-04 papers

Front Immunol. 2025 ;16 1521708

Immune biomarkers in circulating cells of NSCLC patients can effectively evaluate the efficacy of chemotherapy combined with anti-PD-1 therapy.

Introduction: The application of programmed cell death protein 1 (PD-1) antibodies has brought significant benefits to patients with non-small cell lung cancer (NSCLC). However, not all patients respond to PD-1 immune therapy. The aim of this study was to identify response biomarkers to predict the efficacy of chemotherapy combined with anti-PD-1 therapy in NSCLC patients.
Methods: Thirty-two NSCLC patients receiving chemotherapy combined with anti-PD-1 therapy were recruited, and peripheral blood samples were collected before and after treatment. Flow cytometry was used to detect the proportions of circulating T-cell subsets, and cytokines in the blood serum were detected via ELISA.
Results: The results revealed that, among the CR/PR group (CR, complete response; PR, partial response; n = 22), the proportions of CD3+TIM-3+PD-1+, CD3+CD4+TIM-3+PD-1+, and CD3+CD8+TIM-3+PD-1+, CD3+γδT+PD-1+, CD3+γδT+Vδ1+PD-1+, and CD3+γδT+Vδ2+PD-1+T cells were lower after treatment, with no significant differences found between the stable disease (SD) and progressive disease (PD) groups (n = 10). Some proinflammatory cytokines are highly expressed in patients with NSCLC.
Discussion: This study suggests that monitoring changes in immune biomarkers in the circulating cells of NSCLC patients may help differentiate CR/PR patients from SD/PD patients, providing a potential new approach for assessing the efficacy of chemotherapy combined with anti-PD-1 therapy.

Keywords: NSCLC; TIM-3; anti-PD-1 therapy; cytokines; immune biomarkers

DOI: https://doi.org/10.3389/fimmu.2025.1521708

Nat Commun. 2025 May 02. 16(1): 4112

LKB1 regulates JNK-dependent stress signaling and apoptotic dependency of KRAS-mutant lung cancers.

The efficacy of molecularly targeted therapies may be limited by co-occurring mutations within a tumor. Conversely, these alterations may confer collateral vulnerabilities that can be therapeutically leveraged. KRAS-mutant lung cancers are distinguished by recurrent loss of the tumor suppressor STK11/LKB1. Whether LKB1 modulates cellular responses to therapeutic stress seems unknown. Here we show that in LKB1-deficient KRAS-mutant lung cancer cells, inhibition of KRAS or its downstream effector MEK leads to hyperactivation of JNK due to loss of NUAK-mediated PP1B phosphatase activity. JNK-mediated inhibitory phosphorylation of BCL-XL rewires apoptotic dependencies, rendering LKB1-deficient cells vulnerable to MCL-1 inhibition. These results uncover an unknown role for LKB1 in regulating stress signaling and mitochondrial apoptosis independent of its tumor suppressor activity mediated by AMPK and SIK. Additionally, our study reveals a therapy-induced vulnerability in LKB1-deficient KRAS-mutant lung cancers that could be exploited as a genotype-informed strategy to improve the efficacy of KRAS-targeted therapies.

DOI: https://doi.org/10.1038/s41467-025-58753-y

Int Immunopharmacol. 2025 May 01. pii: S1567-5769(25)00729-5. [Epub ahead of print]157 114739

Xiaoyang Hua, Yaopeng Wang, Chuanxiao Wang, Haoxian Yang, Anbang Liu.

Lung adenocarcinoma (LUAD) is the most prevalent subtype of lung cancer, yet targeted and immune therapeutic strategies remain limited. DNA damage-inducible transcript 4 (DDIT4) is one of the hypoxia-related genes, and its role in tumors has begun to gain attention. However, the specific mechanism of DDIT4 in LUAD is still unclear. Therefore, in-depth exploration of its role and mechanism in LUAD has high clinical value and innovative significance, and can provide a new direction for the diagnosis and treatment of LUAD. Bioinformatics analysis identified DDIT4 as a poor prognostic factor positively correlated with epithelial-mesenchymal transition (EMT). Tumors with high DDIT4 expression exhibited increased immune infiltration and significantly higher levels of immune checkpoint genes, including PD-L1 and PD-1. Drug sensitivity analysis suggested that DDIT4 could serve as a predictive biomarker for LUAD therapy response. Experimental validation demonstrated that DDIT4 expression was significantly upregulated in LUAD tissues and further induced under hypoxic conditions. Pathway enrichment analyses indicated that DDIT4 may regulate LUAD progression via the MAPK/ERK signaling pathway. Functional experiments confirmed that DDIT4 promotes LUAD cell migration, invasion, and EMT through this pathway. Rescue experiments further validated the mechanistic role of DDIT4, and in vivo studies confirmed its ability to enhance LUAD metastasis. In conclusion, DDIT4 functions as a prognostic biomarker and therapeutic target in LUAD by modulating EMT and metastasis through MAPK/ERK signaling. Its association with immune infiltration and therapy response suggests that targeting DDIT4 may enhance immunotherapy and personalized treatment strategies for LUAD patients.

Keywords: DDIT4; EMT; Hypoxia; Lung adenocarcinoma; MAPK/ERK signaling pathway

DOI: https://doi.org/10.1016/j.intimp.2025.114739