2025年 · 第03卷第03期

最常见的妇科恶性肿瘤包括宫颈癌、卵巢癌、子宫内膜癌和外阴癌，所有这些都是女性死亡的主要原因。^1,2,3与其他癌症类似，妇科肿瘤可以使用各种方法进行治疗，包括手术、放疗、化疗和免疫治疗。为这些患者确定最有效的治疗方法至关重要。应该使用单一治疗方式还是采用多种疗法的组合？应积极探索基于肿瘤发展不同机制的新治疗方案。肿瘤复发和转移是影响患者预后的显著因素。迄今为止，还没有解决复发和转移的最佳解决方案。因此，需要更多的研究和临床试验来阐明所涉及的具体机制，并为疾病治疗提供新的见解。为了更好地了解妇科肿瘤基础研究、诊断、治疗的现状和最新进展，我们组织了本期专刊，题目是《妇科肿瘤研究的现状和最新进展》。

肺癌是全世界癌症相关死亡的主要原因之一。¹非小细胞肺癌（NSCLC）约占肺癌病例的85%，²而小细胞肺癌(SCLC)约占病例的15%。³传统化疗和放疗在一定程度上提高了患者生存率，但仍有不少患者面临高复发率和不良预后。因此，肺癌的研究和治疗仍然面临重大挑战。尽管存在弊端，但化疗药物使用历史悠久，疗效可靠的支持证据和广泛的抗肿瘤谱，使其成为最常用的抗肿瘤药物和抗肿瘤治疗的基石。近年来，免疫检查点抑制剂（ICIs）（如程序性细胞死亡蛋白1[PD-1]和程序性细胞死亡配体1[PD-L1]抑制剂）和靶向疗法的兴起为肺癌的治疗带来了新的希望。本期特刊名为《肺癌研究最新进展》，重点介绍肺癌临床研究的最新进展和治疗相关不良反应，以改善肺癌患者的预后，减少药物治疗后的不良反应。

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.

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.

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.

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, P_adj = 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%.

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.

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.

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.

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.

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.

Ji等人最近的一篇文章，¹题为“接受放疗和化疗的IVB期宫颈癌患者内脏肥胖与预后的关系”，强调了内脏肥胖对接受放化疗的IVB期宫颈癌患者预后的影响。研究的主要结果是，内脏与皮下脂肪组织面积比（VSR）较高的人存活的机会要高得多。这些结果既有趣又具有临床相关性。这项研究的发现与现有文献一致，这表明身体成分，特别是脂肪分布，显著影响癌症预后。该研究使用计算机断层扫描（CT）来测量内脏和皮下脂肪。这是一种精确而有用的方法来检查一组患者的身体成分，这些患者通常很难管理，因为他们的疾病到目前为止还很严重。

我写这封信是为了评论最近发表在癌症发病机制与治疗Ji等人题为“IVB期宫颈癌放化疗患者内脏肥胖与预后的关系”。¹这项富有洞察力的研究强调了癌症治疗中一个经常被忽视的重要方面，即：身体成分，特别是内脏肥胖对晚期宫颈癌患者预后的影响。本文报道的发现既有趣又重要，值得科学界内外进一步讨论。

出版商感到遗憾的是，Zhong等人的论文“铜突相关lncRNAs的综合分析：揭示前列腺癌的预后意义、免疫微环境和铜诱导的机制”的图4中缺少子集图的标签。癌症发病机制与治疗，第3卷（2025）：48–59。图4应如下所示：