2025年 · 第03卷第03期

Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease with increasing incidences worldwide. The overall 5-year survival rate remains low, underscoring the urgent need for effective therapies. Despite the promising efficacy of immunotherapy for various solid tumors, its benefits for pancreatic cancer have been disappointing. This is largely because of the complex and unique mechanisms of immune evasion inherent in PDAC. Emerging evidence has highlighted the pivotal role of tumor-associated macrophages (TAMs) in facilitating the immune escape of PDAC. TAMs significantly contribute to forming an immunosuppressive microenvironment, which hinders the effectiveness of immunotherapeutic approaches. They achieve this through multiple pathways, including the secretion of cytokines and the promotion or inhibition of multiple immune cells. In this review, we summarized the main pathways through which TAMs form an immunosuppressive microenvironment in PDAC. We also examined the current status and recent progress of immunotherapy strategies that specifically target macrophages. By understanding these mechanisms and exploring targeted therapies, we aimed to shed light on potential avenues for improving the treatment outcomes of this devastating disease.

Breast cancer (BC) continues to be the primary malignant neoplasm affecting women. For many years, traditional approaches such as chemotherapy, hormone therapy, radiation, and surgical interventions have been employed to treat BC. However, these therapies often fall short due to considerable adverse effects and the development of multidrug resistance or tolerance. Spices and culinary herbs that have been utilized in culinary practices for millennia have also demonstrated therapeutic effects in traditional medicinal practices serving to both prevent and treat BC. This review aims to comprehensively explore the roles and underlying mechanisms through which spices and culinary herbs exert anti-BC properties. These natural ingredients exhibit diverse anti-BC effects that encompass diverse mechanisms, including the inhibition of BC cell proliferation, migration, metastasis, and angiogenesis, as well as the induction of cell cycle arrest and apoptosis. These actions are achieved by targeting signaling pathways such as phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR), notch signaling, Hedgehog signaling, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and Wingless/int (Wnt)/β-catenin signaling pathways that are predominantly overexpressed in breast tumors or are exploited by them to promote cancer progression. Additionally, compounds such as curcumin, allicin, gingerol, zerumbone, diosgenin, capsaicin, piperine, quercetin, malabaricone C, eugenol, cardamomin, carnosol, cinnamaldehyde, sinigrin present in these spices and herbs may be more effective with reduced side effects against BC compared to conventional chemotherapeutic drugs. This review presents a concise overview of the potential contributions of spices, culinary herbs, and their potent bioactive constituents against BC, with particular emphasis on elucidating their mechanisms of action.

Epithelial-mesenchymal transition (EMT) is a biological process that involves the transformation of epithelial cells into cells with a mesenchymal phenotype, enhancing their migratory and invasive capabilities. EMT is crucial in embryonic development, tissue healing, and wound repair, and aids in forming diverse cell types and structures. However, aberrant EMT is involved in pathogenic processes, including fibrosis, cancer development, and progression. Recent studies show that EMT contributes to resistance to cancer treatment, including epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy in non-small cell lung cancer (NSCLC). This review discusses the intricate relationship between EMT and acquired chemoresistance to EGFR-TKIs. It details evidence on how EGFR-TKIs might induce EMT and how EMT may cause EGFR-TKI resistance. Understanding these pathways is crucial for developing effective prognostic and therapeutic strategies to predict and combat acquired chemoresistance in NSCLC, advancing the field toward more targeted and personalized treatment approaches.

Copper (Cu) is an indispensable micronutrient that maintains signaling pathways and biological homeostasis in almost all cell types; however, its excess affects the tricarboxylic acid cycle, causes the accumulation of fatty acylated proteins, destabilization of iron-sulfur cluster proteins, and increases the levels of intracellular reactive oxygen species, leading to proteotoxic stress and cell death. Cuproptosis, a form of Cu-dependent cell death, differs from other types of regulated cell death (RCD) and was first reported in Science in 2022. Recently, the RCD pathways have been targeted in cancer therapy. However, the escape of apoptosis in tumor cells causes resistance to treatment and tumor recurrence. Therefore, there is an urgent need to study the alternative mechanisms of cancer cell mortality. Compared to normal patients, a significant increase in serum Cu ion levels has been observed in patients with tumors. Moreover, tumor cell proliferation, angiogenesis, and metastasis are associated with cuproptosis. Thus, exploring cancer signaling pathways related to cuproptosis will provide a new perspective for the development of anti-cancer drugs. Importantly, cuproptosis is closely associated with the modulation of anti-tumor immunity. The expression of cuproptosis-related genes (CRGs) is significantly correlated with immune cell infiltration and the immune checkpoint programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1). Based on these findings, a series of cuproptosis-related drugs have been used in tumor-targeted combination therapy or as immune synergists. Therefore, elucidating the role of cuproptosis per cancer stage and in the tumor immune microenvironment (TIME) is helpful in clarifying the potential value of Cu in the treatment of specific cancers. In this review, we summarize specific cancer signaling pathways related to cuproptosis and cancer treatment based on the regulation of Cu concentration. The combination of these two approaches may help researchers develop more therapies targeting cuproptosis-related pathways. Importantly, we focused on the effect of cuproptosis on the TIME and systematically discussed the role of CRGs in tumor immunity considering CRG-related anti-tumor immune signaling pathways, tumor prognosis scoring system, anti-tumor immunotherapy, and biological experiments and bioinformatics prediction models, to provide new ideas for the development of anticancer therapy targeting cuproptosis-related pathways.

Background: Tryptophan metabolism is involved in esophageal carcinogenesis. However, its genetic mechanisms remain unclear. This study aimed to investigate the effect of genetic variants that encode tryptophan metabolism on susceptibility to esophageal cancer (EC) and elucidate the mechanisms underlying genetic variation in EC progression. Methods: Age- and sex-matched cohorts of 167 patients with EC and 236 healthy controls were enrolled in this study. The concentrations of tryptophan and its metabolites were determined by self-assembled high-performance liquid chromatography-tandem mass spectrometry. High-throughput sequencing techniques were utilized to detect candidate coding genetic variants, and dominant genetic models were used to elucidate the genotypic associations. Results: Tryptophan metabolism was significantly imbalanced in patients with EC, with elevated indolepropionic acid (IPA) levels reducing the risk of EC susceptibility. ACSM2B rs73530508 (A > G) mutation was associated with higher IPA levels in vivo (P = 0.0004, false discovery rate [FDR] = 0.0092) and significantly reduced the risk of EC susceptibility (odds ratio [OR]: 0.576, Padj = 0.0161). Mediation effect analysis indicated that single-nucleotide polymorphism may inhibit carcinogenesis by reducing IPA metabolism and excretion with a mediation effect of 45.54%. Conclusions: This study identifies the potential mechanism of ACSM2B rs73530508 (A > G) in esophageal carcinogenesis and its role in driving increased IPA levels, thereby suppressing the risk of development.

Background: Gastric cancer (GC) is a common malignancy characterized by the absence of reliable prognostic indicators and effective therapeutic targets. Claudin-9 (CLDN9) has been demonstrated to be upregulated in various cancers. However, its prognostic value, biological function, and regulatory mechanisms in GC remain unclear. Therefore, this study aimed to elucidate the role of CLDN9 in GC progression and its underlying mechanisms. Methods: We utilized consensus cluster, random survival forest, and multivariate Cox regression analyses to identify CLDN9 in GC. Subsequently, we evaluated the mRNA and protein levels of CLDN9 in GC using quantitative real-time polymerase chain reaction (PCR) (qRT-PCR), Western blotting (WB), and immunohistochemistry (IHC). Furthermore, the role of CLDN9 in GC progression was investigated using a series of functional in vivo and in vitro experiments. Finally, we elucidated the molecular mechanisms of CLDN9 using bioinformatics, molecular biology, animal models, and patient tissue specimens. Results: Two GC subtypes with survival and functional differences were identified based on glycolytic metabolic genes in the Cancer Genome Atlas (TCGA)-Stomach adenocarcinoma (STAD) dataset. A prognostic risk score was calculated using seven genes to assess the overall survival (OS) in GC. Using random survival forest and multivariate Cox analyses, we identified CLDN9 as the key gene linked to the glycolytic subtype and prognosis of GC. CLDN9 expression was significantly upregulated in patients with GC as well as in GC cells. CLDN9 knockdown inhibited tumor proliferation, invasion, and metastasis both in vivo and in vitro. Mechanistically, CLDN9 was found to regulate lactate dehydrogenase A (LDHA) expression and promote glycolytic metabolism by activating the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/hypoxia-inducible factor 1-alpha (HIF1α) signaling pathway. Additionally, lactate, a glycolytic metabolite, enhanced programmed cell death ligand 1 (PD-L1) lactylation and stability, which suppressed anti-tumor immunity in CD8+ T cells, thereby contributing to GC progression. Conclusions: CLDN9 expression is associated with GC development and progression. Mechanistically, CLDN9 enhances the glycolysis pathway and facilitates PD-L1 lactylation through the PI3K/AKT/HIF1α signaling pathway, thereby suppressing anti-tumor immunity in CD8+ T cells. CLDN9 has the potential to serve as a novel prognostic marker and therapeutic target for GC.