Background: Immunotherapy for gastric cancer remains a challenge due to its limited efficacy. Metabolic reprogramming toward glycolysis has emerged as a promising avenue for enhancing the sensitivity of tumors to immunotherapy. Pyruvate dehydrogenase kinases (PDKs) play pivotal roles in regulating glycolysis. The importance of PDKs in the context of gastric cancer immunotherapy and their potential as therapeutic targets have not been fully explored. Methods: PDK and PD-L1 expression was analyzed using data from the GSE66229 and The Cancer Genome Atlas (TCGA) cohorts. Additionally, the Immune Checkpoint Blockade Therapy Atlas (ICBatlas) database was utilized to assess PDK expression in an immune checkpoint blockade (ICB) therapy group. Subsequently, the upregulation of PD-L1 and the enhancement of anticancer effects achieved by targeting PDK were validated through in vivo and in vitro assays. The impact of PDK on histone acetylation was investigated using ChIP‒qPCR to detect changes in histone acetylation levels. Results: Our analysis revealed a notable negative correlation between PD-L1 and PDK expression. Downregulation of PDK led to a significant increase in PD-L1 expression. PDK inhibition increased histone acetylation levels by promoting acetyl-CoA generation. The augmentation of acetyl-CoA production and concurrent inhibition of histone deacetylation were found to upregulate PD-L1 expression in gastric cancer cells. Additionally, we observed a significant increase in the anticancer effect of PD-L1 antibodies following treatment with a PDK inhibitor. Conclusions: Downregulation of PDK in gastric cancer cells leads to an increase in PD-L1 expression levels, thus potentially improving the efficacy of PD-L1 immune checkpoint blockade therapy.

The primary objective of this study was to examine whether ARID1A mutations confer a fitness advantage to gastric cancer from an immunological perspective, along with elucidating the underlying mechanism. Additionally, we aimed to identify the clinical potential of combining epigenetic inhibitors with immune checkpoint inhibitors to improve the efficacy of immunotherapy for gastric cancer. The correlation between ARID1A gene expression and gastric cancer patient survival was analyzed using the GEO dataset GSE62254. The association between chemokines (CXCL9, CXCL10) and ARID1A was conducted using GSE15460 dataset. Real-time PCR was employed for gene expression analysis, while chromatin immunoprecipitation was used to identify transcriptional regulation on target genes. Protein expression and regulation were assessed through various techniques, including Western blot, ELISA, immunohistochemistry, and immunofluorescence. Chromatin DNA accessibility was determined through MNase digestions, transmission electron microscopy, and ChIP-seq. The impact of ARID1A expression and epigenetic inhibitors on tumor immunity in mice was assessed using flow cytometry. ARID1A expression demonstrated a positive correlation with CD8+ T cell infiltration and clinical prognosis. The loss of ARID1A expression led to impaired Th1-type chemokines. Additionally, ARID1A depletion was associated with enhanced tumor growth and the absence of CD8+ T cells within the tumor microenvironment. The study revealed that ARID1A played a role in promoting histone acetylation and facilitating chromatin accessibility. Notably, the application of deacetylase inhibitors effectively reversed the effects of ARID1A depletion on tumor progression and significantly enhanced the efficacy of immunotherapy. Gastric cancer with ARID1A mutations modulates immune cell chemotaxis within the tumor microenvironment by influencing histone acetylation. Deacetylase inhibitors have the potential to alter the secretion of chemokines for tumor immune cells, consequently enhancing the effectiveness of immune checkpoint inhibitor therapy in ARID1A-mutated gastric cancer.

Cancer cells are characterized by their altered energy metabolism. A hallmark of cancer metabolism is aerobic glycolysis, also called the Warburg effect. Hexokinase 2 (HK2), a crucial glycolytic enzyme converting glucose to glucose-6-phosphate, has been identified as a central player in the Warburg effect. Deletion of HK2 decreases cancer cell proliferation in animal models without explicit side effects, suggesting that targeting HK2 is a promising strategy for cancer therapy. In this study, we discovered a correlation between HK2 and the tumor immune response in triple-negative breast cancer. Inhibition of HK2 led to a reduction in G-CSF expression in 4T1 cells and a decrease in the development of myeloid-derived suppressor cells which, in turn, enhanced T cell immunity and prolonged the survival of 4T1 tumor-bearing mice. Furthermore, the HK2 inhibitor 3-BrPA improved the therapeutic efficacy of anti-PD-L1 therapy in 4T1 tumor-bearing mouse models. This study highlights the potential of glycolysis-targeting interventions as a novel treatment strategy, which can be combined with immunotherapy for the treatment of triple-negative breast cancer.

Background: Hypoxia in the tumor microenvironment (TME) plays a pivotal role in the progression and prognosis of colorectal cancer (CRC). However, effective methods for assessing TME hypoxia remain lacking. This study aims to develop a novel hypoxia-related prognostic score (HPS) based on hypoxia-associated genes to improve CRC prognostication and inform treatment strategies.Methods: Transcriptomic data from CRC patients were analyzed using Lasso regression to identify hypoxia-associated genes with the strongest prognostic significance. The identified genes were validated in vitro by assessing their expression under normoxic and hypoxic conditions in normal intestinal epithelial cells and CRC tumor cell lines. Functional relevance was explored through differential gene expression analysis, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, and protein-protein interaction (PPI) network construction. The association of HPS with extracellular matrix (ECM) composition, immune cell infiltration, and immune suppression was also investigated.Results: Seven hypoxia-associated signature genes were identified, each demonstrating a strong correlation with CRC prognosis. The hypoxia-related prognostic score (HPS), derived from these genes, was significantly linked to changes in the TME. Specifically, HPS values were associated with alterations in ECM composition and distinct immune cell infiltration patterns. Higher HPS values corresponded to increased infiltration of immune-suppressive cells and reduced presence of anti-tumor immune cells. This imbalance promoted an immune-suppressive TME, facilitating tumor progression and immune evasion.Conclusions: The hypoxia-related prognostic score (HPS) captures the regulatory influence of TME hypoxia on immune responses, offering valuable insights into its role in tumor progression. HPS holds promise as a prognostic tool and a guide for developing personalized treatment strategies in CRC.

Objective This study aims to evaluate bowel and urogenital function in patients with locally advanced low rectal cancer treated with immunotherapy combined with neoadjuvant therapy followed by surgery, compared to surgery alone. Methods We conducted a retrospective analysis of 162 patients with locally advanced low rectal cancer treated at Union Hospital, affiliated with Tongji Medical College, Huazhong University of Science and Technology, from May 2021 to May 2024. Seventy-three patients underwent short-course radiotherapy combined with chemotherapy and immunotherapy followed by surgery (SCRT-CIT group), while 89 patients received surgery alone (non-SCRT-CIT group). Standardized questionnaires assessed bowel and urogenital function. Logistic regression analysis was used to identify independent predictors of functional outcomes. Results The incidence of major low anterior resection syndrome (LARS) was significantly higher in the SCRT-CIT group (59.0%) compared to the non-SCRT-CIT group (9.2%). Multivariate analysis identified SCRT-CIT as an independent risk factor for bowel dysfunction (odds ratio [OR] = 10.45, 95% confidence interval [CI], 4.63 ~ 23.57, P < 0.001). SCRT-CIT was also associated with an increased risk of erectile dysfunction in men (OR = 6.51, 95% CI, 1.90 ~ 22.35, P = 0.003) and reduced sexual duration (P = 0.003). In women, SCRT-CIT correlated with a higher prevalence of dyspareunia (P = 0.004) and reduced sexual satisfaction (P = 0.003). Conclusion SCRT-CIT combined with surgery is associated with a significantly higher risk of bowel dysfunction, male erectile dysfunction, reduced sexual duration, and female sexual impairments, including dyspareunia and diminished sexual satisfaction. These findings underscore the importance of comprehensive functional assessments and individualized management for patients undergoing SCRT-CIT for locally advanced low rectal cancer.

Objective This study aims to evaluate bowel and urogenital function in patients with locally advanced low rectal cancer treated with immunotherapy combined with neoadjuvant therapy followed by surgery, compared to surgery alone. Methods We conducted a retrospective analysis of 162 patients with locally advanced low rectal cancer treated at Union Hospital, affiliated with Tongji Medical College, Huazhong University of Science and Technology, from May 2021 to May 2024. Seventy-three patients underwent short-course radiotherapy combined with chemotherapy and immunotherapy followed by surgery (SCRT-CIT group), while 89 patients received surgery alone (non-SCRT-CIT group). Standardized questionnaires assessed bowel and urogenital function. Logistic regression analysis was used to identify independent predictors of functional outcomes. Results The incidence of major low anterior resection syndrome (LARS) was significantly higher in the SCRT-CIT group (59.0%) compared to the non-SCRT-CIT group (9.2%). Multivariate analysis identified SCRT-CIT as an independent risk factor for bowel dysfunction (odds ratio [OR] = 16.31, 95% confidence interval [CI] 6.69–39.77, P < 0.001). SCRT-CIT was also associated with an increased risk of erectile dysfunction in men (OR = 5.49, 95% CI 1.92–15.70, P = 0.001) and reduced sexual duration (P = 0.003). In women, SCRT-CIT correlated with a higher prevalence of dyspareunia (P = 0.004) and reduced sexual satisfaction (P = 0.003). Conclusion SCRT-CIT combined with surgery is associated with a significantly higher risk of bowel dysfunction, male erectile dysfunction, reduced sexual duration, and female sexual impairments, including dyspareunia and diminished sexual satisfaction. These findings underscore the importance of comprehensive functional assessments and individualized management for patients undergoing SCRT-CIT for locally advanced low rectal cancer.