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.
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.
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.
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.
Copyright © 2025 Cao, Zhang, Guo, Wu, Guo, Zhang, Zhang, Liu, Li, Yang, He, Bai, Lv, Xie, Huang, Xiao, Deng, Li, Zhu, Jia, Yin and Wang.

Despite success in treating some hematological malignancies, CAR-T cells have not yet produced similar outcomes in solid tumors due, in part, to the tumor microenvironment, poor persistence, and a paucity of suitable target antigens. Importantly, the impact of the CAR components on these challenges remains focused on the intracellular signaling and antigen-binding domains. In contrast, the flexible hinge and transmembrane domains have been commoditized and are the least studied components of the CAR. Here, we compared the hinge and transmembrane domains derived from either the CD8ɑ or CD28 molecule in identical GUCY2C-targeted third-generation designs for colorectal cancer. While these structural domains do not contribute to differences in antigen-independent contexts, such as CAR expression and differentiation and exhaustion phenotypes, the CD8ɑ structural domain CAR has a greater affinity for GUCY2C. This results in increased production of inflammatory cytokines and granzyme B, improved cytolytic effector function with low antigen-expressing tumor cells, and robust anti-tumor efficacy in vivo compared with the CD28 structural domain CAR. This suggests that CD8α structural domains should be considered in the design of all CARs for the generation of high-affinity CARs and optimally effective CAR-T cells in solid tumor immunotherapy.

This study sought to elucidate the mechanisms underlying the impact of the interferon signaling pathway on Ferroptosis in tumor cells and its correlation with CD8 + T cell exhaustion. Using mouse models and single-cell sequencing, the researchers studied the interaction between CD8 + T cells and the interferon signaling pathway. Differential gene analysis revealed key genes involved in CD8 + T cell exhaustion, and their downstream factors were explored using bioinformatics tools. The expression levels of interferon-related genes associated with Ferroptosis were analyzed using data from the TCGA database, and their relevance to tumor tissue Ferroptosis and patients' prognosis was determined. In vitro experiments were conducted to measure the levels of IFN-γ, MDA, and LPO, as well as tumor cell viability and apoptosis. In vivo validation using a mouse tumor model confirmed the results obtained from the in vitro experiments, highlighting the potential of silencing HSPA6 or DNAJB1 in enhancing the efficacy of PD-1 therapy and inhibiting tumor growth and migration.
© 2024. The Author(s).

Hepatocellular carcinoma (HCC) is a common malignant tumor with a complex immune evasion mechanism posing a challenge to treatment. The role of the S100A10 gene in various cancers has garnered significant attention. This study aims to elucidate the impact of S100A10 on CD8+ T cell exhaustion via the cPLA2 and 5-LOX axis, thereby elucidating its role in immune evasion in HCC. By analyzing the HCC-related data from the GEO and TCGA databases, we identified differentially expressed genes associated with lipid metabolism and developed a prognostic risk model. Subsequently, through RNA-seq and PPI analyses, we determined vital lipid metabolism genes and downstream factors S100A10, ACOT7, and SMS, which were significantly correlated with CD8+ T cell infiltration. Given the most significant expression differences, we selected S100A10 for further investigation. Both in vitro and in vivo experiments were conducted, including co-culture experiments of CD8+ T cells with MHCC97-L cells, Co-IP experiments, and validation in an HCC mouse model. S100A10 was significantly overexpressed in HCC tissues and potentially regulates CD8+ T cell exhaustion and lipid metabolism reprogramming through the cPLA2 and 5-LOX axis. Silencing S100A10 could inhibit CD8+ T cell exhaustion, further suppressing immune evasion in HCC. S100A10 may activate the cPLA2 and 5-LOX axis, initiating lipid metabolism reprogramming and upregulating LTB4 levels, thus promoting CD8+ T cell exhaustion in HCC tissues, facilitating immune evasion by HCC cells, ultimately impacting the growth and migration of HCC cells. This research highlights the critical role of S100A10 via the cPLA2 and 5-LOX axis in immune evasion in HCC, providing new theoretical foundations and potential targets for diagnosing and treating HCC.
© 2024. The Author(s).

Chimeric antigen receptor (CAR) T cells have been used to successfully treat various blood cancers, but adverse effects have limited their potential. Here, we developed chimeric adaptor proteins (CAPs) and CAR tyrosine kinases (CAR-TKs) in which the intracellular ζ T cell receptor (TCRζ) chain was replaced with intracellular protein domains to stimulate signaling downstream of the TCRζ chain. CAPs contain adaptor domains and the kinase domain of ZAP70, whereas CAR-TKs contain only ZAP70 domains. We hypothesized that CAPs and CAR-TKs would be more potent than CARs because they would bypass both the steps that define the signaling threshold of TCRζ and the inhibitory regulation of upstream molecules. CAPs were too potent and exhibited high tonic signaling in vitro. In contrast, CAR-TKs exhibited high antitumor efficacy and significantly enhanced long-term tumor clearance in leukemia-bearing NSG mice as compared with the conventional CD19-28ζ-CAR-T cells. CAR-TKs were activated in a manner independent of the kinase Lck and displayed slower phosphorylation kinetics and prolonged signaling compared with the 28ζ-CAR. Lck inhibition attenuated CAR-TK cell exhaustion and improved long-term function. The distinct signaling properties of CAR-TKs may therefore be harnessed to improve the in vivo efficacy of T cells engineered to express an antitumor chimeric receptor.