TNFR2⁺ regulatory T cells preferentially accumulate in the tumor microenvironment, express high levels of immunosuppressive molecules and possess strong suppressive activity. Our study aimed to explore the characteristics and role of TNFR2⁺ Tregs in the microenvironment and progression of gastric cancer via polychromatic immunofluorescence, single‐cell RNA sequencing and flow cytometry assays. The TNFR2⁺ Treg infiltration level in the tumor microenvironment increased significantly as gastric cancer progressed and was demonstrated to be a prognostic marker. Single‐cell RNA sequencing revealed high levels of TNFR2 in tumor‐infiltrating Tregs. The TNF‐α/TNFR2 signaling pathway was activated, accompanied by the upregulation of costimulatory molecules. Unlike blood Tregs, tumor‐infiltrating Tregs existed in activated and effector states. In addition to expressing costimulatory molecules such as TNFR2, 4‐1BB, OX40 and GITR, tumor‐infiltrating Tregs were also characterized by high expression levels of immune checkpoints such as CTLA‐4 and TIGIT and chemokines such as CCR6. In vitro studies showed that the TNF‐α/TNFR2 pathway increased the Foxp3 expression in CD4⁺CD25⁺ T cells and the latent TGF‐β production in Tregs as well as enhanced the immunosuppressive function of Tregs. In summary, our study revealed high infiltration levels of TNFR2⁺ Tregs that were in activated and effector states in the tumor microenvironment. The infiltration level of TNFR2⁺ Tregs is a prognostic marker and an independent risk factor for gastric cancer. Activation of the TNF‐α/TNFR2 pathway promotes the immunosuppressive phenotype and function of Tregs. Our study provides a new theoretical basis for TNFR2⁺ Tregs as a therapeutic target in gastric cancer.

Tumor necrosis factor-alpha (TNF-α) is a pleiotropic inflammatory cytokine produced mainly by activated macrophages, lymphocytes and other cell types. Two distinct forms of TNF-α have been identified: soluble TNF-α (sTNF-α) and transmembrane TNF-α (mTNF-α). mTNF-α, which is the precursor of sTNF-α, can be cleaved by the TNF-α converting enzyme (TACE) and is released as sTNF-α. sTNF-α binds primarily to TNF receptor 1 (TNFR1) and plays an important role in the inflammatory immune response, whereas mTNF-α interacts primarily with TNF receptor 2 (TNFR2) and mediates the promotion of cellular proliferation and survival and other biological effects. It has been reported that the interaction between mTNF-α and TNFR2 induces bi-directional (forward and reverse) signaling in both mTNF-α- and TNFR2-expressing cells. Increasing evidence shows that the forward and reverse signaling mediated by mTNF-α and TNFR2 might play a significant role in the tumor microenvironment. In this review, the role of the crosstalk between mTNF-α and TNFR2 in the tumor microenvironment will be discussed.

Foxp3⁺ T_regs have been known as a major regulator of immune homeostasis through their immunosuppressive function. Th17 lineage is a CD4⁺ T cell subset that exerts its function by secreting proinflammatory cytokines and protecting host against microbial infections. The altered ratio between Foxp3⁺ T_regs and Th17 cells plays an important role in the pathogenesis of immune-related diseases. Recent mice and human studies have demonstrated that T_regs can be reprogrammed into a novel population, IL-17⁺Foxp3⁺ T cells, phenotypically and functionally resembling Th17 cells under the complicated cytokine stimulation. The identification of IL-17⁺Foxp3⁺ T cells may provide a new understanding of therapy targeting T_regs and Th17 cells in autoimmune diseases and cancer. Here, we highlight significant data regarding the phenotype profile, origination, differentiation, and the pleiotropic functions of IL-17⁺Foxp3⁺ T cells and the reciprocal relationships of these cells to T_regs and Th17 cells. Furthermore, the role of IL-17⁺Foxp3⁺ T cells in tumorigenesis and clinical implications in cancer therapy are discussed in this review.

Conventional immunotherapy exhibits low response rates due to the immunosuppressive tumor microenvironment (TME). To overcome this limitation, this study introduces ZFPG nanoparticles (ZFPG NPs) with ZnFe₂O₄@Pt cores and glucose oxidase (GOx) shells. The ZFPG NPs possess five-enzyme activities, good sonosensitivity, and remarkable magnetic targeting properties, which facilitate sono-metallo-immunotherapy for prostate cancer treatment in male mice. Specifically, the magnetic targeting ability effectively improves their accumulation in tumors while still showing enrichment in the liver and kidneys. The multienzyme cascade catalysis and sonosensitivity of these NPs effectively deplete glutathione and glucose, and enhance the generation and utilization of H₂O₂, thereby inducing multiple ROS bursts. Furthermore, these comprehensive effects up-regulate the HMOX1 to promote the Fe²⁺ and lipid peroxides accumulation, thereby inducing immunogenic ferroptosis. This strategy facilitates anti-tumor immunity by ameliorating the immunosuppressive TME and inhibiting lung metastatic progression. This joint warfare strategy offers a powerful solution to address conventional immunotherapy limitations.

Gastric cancer (GC) is a prevalent malignant cancer of digestive system. To identify key genes in GC, mRNA microarray GSE27342, GSE29272, and GSE33335 were downloaded from GEO database. Differentially expressed genes (DEGs) were obtained using GEO2R. DAVID database was used to analyze function and pathways enrichment of DEGs. Protein-protein interaction (PPI) network was established by STRING and visualized by Cytoscape software. Then, the influence of hub genes on overall survival (OS) was performed by the Kaplan-Meier plotter online tool. Module analysis of the PPI network was performed using MCODE. Additionally, potential stem loop miRNAs of hub genes were predicted by miRecords and screened by TCGA dataset. Transcription factors (TFs) of hub genes were detected by NetworkAnalyst. In total, 67 DEGs were identified; upregulated DEGs were mainly enriched in biological process (BP) related to angiogenesis and extracellular matrix organization and the downregulated DEGs were mainly enriched in BP related to ion transport and response to bacterium. KEGG pathways analysis showed that the upregulated DEGs were enriched in ECM-receptor interaction and the downregulated DEGs were enriched in gastric acid secretion. A PPI network of DEGs was constructed, consisting of 43 nodes and 87 edges. Twelve genes were considered as hub genes owing to high degrees in the network. Hsa-miR-29c, hsa-miR-30c, hsa-miR-335, hsa-miR-33b, and hsa-miR-101 might play a crucial role in hub genes regulation. In addition, the transcription factors-hub genes pairs were displayed with 182 edges and 102 nodes. The high expression of 7 out of 12 hub genes was associated with worse OS, including COL4A1, VCAN, THBS2, TIMP1, COL1A2, SERPINH1, and COL6A3. The miRNA and TFs regulation network of hub genes in GC may promote understanding of the molecular mechanisms underlying the development of gastric cancer and provide potential targets for GC diagnosis and treatment.