In recent years the crucial role of CD4⁺ T cells in tumor immunomodulation has garnered increasing recognition. While conventional cancer immunotherapy research has predominantly focused on the cytotoxic function of CD8⁺ T cells, emerging evidence has now shown that CD4⁺ T cells enhance antitumor immunity by delivering co-stimulatory signals, secreting cytokines, and promoting cytotoxic T lymphocyte (CTL) activation and display unique immunoregulatory capabilities through direct tumor cell killing or remodeling of the tumor microenvironment. The high heterogeneity and functional plasticity of CD4⁺ T cell subsets significantly influence clinical responses to immunotherapy with underlying mechanisms involving multi-level regulatory networks, including epigenetic modulation and metabolic reprogramming. Deciphering the functional heterogeneity of CD4⁺ T cells and the interactions with the tumor microenvironment will provide essential mechanistic insights for next-generation immunotherapies, such as immune checkpoint inhibitors and chimeric antigen receptor T (CAR-T) therapies, thereby advancing personalized treatment paradigms.

Gastric signet ring cell carcinoma (GSRCC) is a distinct subtype of gastric cancer with unique epidemiological and pathogenic characteristics. However, its prognostic features and molecular landscape remain poorly understood, limiting the development of targeted therapies. In this study, we analyzed clinical data from over 10,000 patients with gastric cancer treated at Zhejiang Cancer Hospital between January 2010 and December 2019. A comprehensive proteomic analysis was conducted on 112 GSRCC patients with a signet ring cell content exceeding 70%, identifying 7322 proteins. This study established a tissue-specific peptide spectral library, representing the most extensive proteomic atlas of GSRCC to date. We identified four novel proteomic subtypes: metabolism, microenvironment dysregulation, migration, and proliferation. Furthermore, PRDX2 and DDX27 emerged as potential prognostic biomarkers, which were further validated in an independent cohort of 75 patients. Molecular profiling of 79 cases that lacked expression of established gastric cancer treatment targets and biomarkers revealed significant tumor heterogeneity. Unsupervised clustering identified three distinct proteomic clusters, with cluster 2 exhibiting the poorest prognosis. Additionally, we identified four potential drug targets, including PFAS, EIF2S3, EIF6, and NFKB2. Molecular docking analysis suggested that neratinib, a clinically approved drug, could serve as a promising therapeutic agent for GSRCC, offering new avenues for clinical intervention.

Gastric cancer (GC) ranks fifth in cancer incidence and fourth in cancer-related mortality worldwide. Reactive oxygen species (ROS) are highly oxidative oxygen-derived products that have crucial roles in cell signaling regulation and maintaining internal balance. ROS are closely associated with the occurrence, development, and treatment of GC. This review summarizes recent findings on the sources of ROS and the bidirectional regulatory effects on GC and discusses various treatment modalities for GC that are related to ROS induction. In addition, the regulation of ROS by natural small molecule compounds with the highest potential for development and applications in anti-GC research is summarized. The aim of the review is to accelerate the clinical application of modulating ROS levels as a therapeutic strategy for GC.