The development of combination immunotherapy based on the mediation of regulatory mechanisms of the tumor immune microenvironment (TIME) is promising. However, a deep understanding of tumor immunology must involve the systemic tumor immune environment (STIE) which was merely illustrated previously. Here, we aim to review recent advances in single-cell transcriptomics and spatial transcriptomics for the studies of STIE, TIME, and their interactions, which may reveal heterogeneity in immunotherapy responses as well as the dynamic changes essential for the treatment effect. We review the evidence from preclinical and clinical studies related to TIME, STIE, and their significance on overall survival, through different immunomodulatory pathways, such as metabolic and neuro-immunological pathways. We also evaluate the significance of the STIE, TIME, and their interactions as well as changes after local radiotherapy and systemic immunotherapy or combined immunotherapy. We focus our review on the evidence of lung cancer, hepatocellular carcinoma, and nasopharyngeal carcinoma, aiming to reshape STIE and TIME to enhance immunotherapy efficacy.

Most colorectal cancer (CRC) patients are insensitive to immune checkpoint inhibitors (ICIs) due to the immunosuppressive tumor microenvironment (TME). Epigenetic factors such as the bromo-and extraterminal domain (BET) family proteins may be responsible for the immunosuppressive microenvironment. Previous studies have shown that inhibitors of BET family proteins have the potential to remodel the immunosuppressive TME. However, data on the role of BET inhibitors in immune microenvironment in CRC remains unclear. Here, we evaluated the immunoregulatory role of JQ1, a BET inhibitor, in CRC. Transcriptome sequencing data showed that JQ1 decreased CD274 expression and increased H2Kb expression in MC38 cells. Flow cytometry assays demonstrated that JQ1 decreased cell-surface PD-L1 expression in MC38 and HCT116 cells. Moreover, JQ1 significantly increased cell-surface expression of major histocompatibility complex class I (MHC-I) in MC38 cells and HCT116 cells. Antigen-specific cytotoxic T lymphocytes (CTLs) assay demonstrated that JQ1 enhanced the MHC-I-mediated cytotoxicity of CTLs. Mouse colon cancer cell line MC38 was used to establish the syngeneic mouse tumor model. Compared with the control, JQ1 significantly inhibited tumor growth and prolonged the overall survival of the mice. Besides, JQ1 did not only inhibit tumor growth by enhancing anti-tumor immunity, but also promoted the anti-tumor effect of PD-1 antibody. In addition, our data showed that JQ1 reduced infiltration of intratumoral regulatory T cells (Treg), thus remodeling the immunosuppressive TME. Taken together, these results highlight a new approach that enhances anti-PD-1 sensitivity in CRC.

Serotonin (5-hydroxytryptamine, 5-HT) and its receptors play important roles in the development and progression of malignant tumors. The effect of the 5-HT receptor 1D (HTR1D), a member of the serotonin receptor family, on gastric cancer (GC) is not clear. Analysis of clinical data has shown that high expression of HTR1D was associated with poor prognosis in patients with GC and was an independent risk factor for reduced overall survival (OS) and disease-free survival (DFS). The present study assessed the effects of HTR1D knockdown and the HTR1D inhibitor GR127935 on the biological behavior of GC cells, which both impaired the proliferation and migration of GC cells. RNA sequencing showed that GR127935 inhibited tumor progression by limiting DNA replication and the cell cycle, inducing ferroptosis, and affecting tumor metabolism. Taken together, these findings showed that HTR1D has a potent oncogenic effect on GC and may provide a novel therapeutic target.

Objective: To estimate the survival and prognosis of patients with thyroid carcinoma (THCA) based on the Long non-coding RNA (lncRNA) traits linked to cuproptosis and to investigate the connection between the immunological spectrum of THCA and medication sensitivity.Methods: RNA-Seq data and clinical information for THCA were obtained from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. We built a risk prognosis model by identifying and excluding lncRNAs associated with cuproptosis using Cox regression and LASSO methods. Both possible biological and immune infiltration functions were investigated using Principal Component Analysis (PCA), Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and immunoassays. The sensitivity of the immune response to possible THCA medicines was assessed using ratings for tumor immune dysfunction and exclusion (TIDE) and tumor mutational burden (TMB).Results: Seven cuproptosis-related lncRNAs were used to construct our prognostic prediction model: AC108704.1, DIO3OS, AL157388.1, AL138767.3, STARD13-AS, AC008532.1, and PLBD1-AS1. Using data from TCGA’s training, testing, and all groups, Kaplan-Meier and ROC curves demonstrated this feature’s adequate predictive validity. Different clinical characteristics have varying effects on cuproptosis-related lncRNA risk models. Further analysis of immune cell infiltration and single sample Gene Set Enrichment Analysis (ssGSEA) supported the possibility that cuproptosis-associated lncRNAs and THCA tumor immunity were closely connected. Significantly, individuals with THCA showed a considerable decline in survival owing to the superposition effect of patients in the high-risk category and high TMB. Additionally, the low-risk group had a higher TIDE score compared with the high-risk group, indicating that these patients had suboptimal immune checkpoint blocking responses. To ensure the accuracy and reliability of our results, we further verified them using several GEO databases.Conclusion: The clinical and risk aspects of cuproptosis-related lncRNAs may aid in determining the prognosis of patients with THCA and improving therapeutic choices.