Induction, growth, drug resistance, and metastasis: A comprehensive summary of the relationship between STAT3 and gastric cancer.

Gastric cancer is a prevalent and highly lethal malignancy that poses substantial challenges to healthcare systems globally. Owing to its often asymptomatic nature in early stages, diagnosis frequently occurs at advanced stages when surgical intervention is no longer a viable option, forcing most patients to rely on nonsurgical treatments such as chemotherapy, targeted therapies, and emerging immunotherapies. Unfortunately, the therapeutic response rates for these treatments are suboptimal, and even among responders, the eventual development of drug resistance remains a significant clinical hurdle. Signal transducer and activator of transcription 3 (STAT3) is a widely expressed cellular protein that plays crucial roles in regulating cellular processes such as growth, metabolism, and immune function. Aberrant activation of the STAT3 pathway has been implicated in the initiation, progression, and therapeutic resistance of several cancers, with gastric cancer being particularly affected. Dysregulated STAT3 signaling not only drives tumorigenesis but also facilitates the development of resistance to chemotherapy and targeted therapies, as well as promotes metastatic dissemination. In this study, we explored the critical role of the STAT3 signaling cascade in the pathogenesis of gastric cancer, its contribution to drug resistance, and its involvement in the metastatic process. Furthermore, we assess recent advances in the development of STAT3 inhibitors and their potential application as therapeutic agents in the treatment of gastric cancer. This work provides a comprehensive overview of the current understanding of STAT3 in gastric cancer and offers a foundation for future research aimed at improving therapeutic outcomes in this challenging disease.

Novel dual inhibitors of PARP and HDAC induce intratumoral STING-mediated antitumor immunity in triple-negative breast cancer.

PARP inhibitors and HDAC inhibitors have been approved for the clinical treatment of malignancies, but acquired resistance of or limited effects on solid tumors with a single agent remain as challenges. Bioinformatics analyses and a combination of experiments had demonstrated the synergistic effects of PARP and HDAC inhibitors in triple-negative breast cancer. A series of novel dual PARP and HDAC inhibitors were rationally designed and synthesized, and these molecules exhibited high enzyme inhibition activity with excellent antitumor effects in vitro and in vivo. Mechanistically, dual PARP and HDAC inhibitors induced BRCAness to restore synthetic lethality and promoted cytosolic DNA accumulation, which further activates the cGAS-STING pathway and produces proinflammatory chemokines through type I IFN-mediated JAK-STAT pathway. Moreover, these inhibitors promoted neoantigen generation, upregulated antigen presentation genes and PD-L1, and enhanced antitumor immunity when combined with immune checkpoint blockade therapy. These results indicated that novel dual PARP and HDAC inhibitors have antitumor immunomodulatory functions in triple-negative breast cancer. Novel dual PARP and HDAC inhibitors induce BRCAness to restore synthetic lethality, activating tumoral IFN signaling via the cGAS-STING pathway and inducing cytokine production, promoting neoantigen generation and presentation to enhance the immune response.

Fatty acid metabolism predicts prognosis and NK cell immunosurveillance of acute myeloid leukemia patients.

Background: Cell metabolic reprogramming is a hallmark of tumor prognosis, and fatty acid metabolism (FAM) plays a crucial role in the tumor microenvironment (TME). However, the relationship between FAM, TME, and prognosis of acute myeloid leukemia (AML) patients remains elusive. Methods: We extracted the single-cell RNA sequencing (scRNA-Seq) and bulk transcriptome data of AML patients from the TCGA and GEO databases and assessed the relationship between FAM, TME, and AML patient prognosis. We also performed functional enrichment (FE) assay to evaluate the significance of FAM in anti-AML immunosurveillance. Results: Our scRNA-Seq analysis revealed that the leukemic stem cell (LSC)-enriched population exhibited elevated levels of FAM-related genes. Using these FAM-related genes, we developed a prognostic model that accurately estimated AML patient outcome. FE analysis showed that FAM was strongly related to alterations of TME-based immunosurveillance in AML patients. More importantly, we demonstrated that FAM inhibition via pharmaceutical targeting of PLA2G4A, a highly expressed FAM gene in AML patients with poor prognosis, enhanced the NK cell-mediated immunosurveillance in leukemia cells. Conclusions: Leukemic stem cell (LSC)-enriched population exhibited elevated levels of FAM-related genes. We have successfully established the FAM formula that predicts AML patient prognosis and alterations in the TME-based immunosurveillance. We also found that PLA2G4A was a highly expressed FAM gene in AML patients with poor prognoses. Pharmaceutical targeting of PLA2G4A increased the expression of NKG2DL in leukemia cells in vitro and thus enhanced the NK cell-mediated immunosurveillance.

Design, synthesis and antitumor evaluation of novel 1H-indole-2-carboxylic acid derivatives targeting 14-3-3η protein.

In this work, a series of novel 1H-indole-2-carboxylic acid derivatives targeting 14-3-3η protein were designed and synthesized for treatment of liver cancer. After structural optimization for several rounds, C11 displayed a relatively better affinity with 14-3-3η, as well as the best inhibitory activities against several typical human liver cancer cell lines, including Bel-7402, SMMC-7721, SNU-387, Hep G2 and Hep 3B cells. Compound C11 also displayed best inhibitory activity against chemotherapy-resistant Bel-7402/5-Fu cells. Besides, C11 was rather safe against hERG and possessed moderate T1/2 and CL values in liver microsomes. In anti-proliferation, trans-well and cell apoptosis assays, C11 also showed its huge potential as a potent antitumor agent. Then, Western blot assay was conducted, following analyzed by molecular docking, the anti-proliferative mechanisms of this small-molecule inhibitor were revealed. Moreover, C11 was demonstrated to induce G1-S phase cell cycle arrest in liver cancer cells.