Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment and play important roles in cancer progression and treatment resistance. Despite recognized heterogeneity among CAFs, their specific contributions to chemoresistance in gastric cancer (GC) remain incompletely understood. This study identifies THY1+ CAFs as a distinct subset associated with poor patient outcomes and oxaliplatin resistance in GC. Both in vitro and in vivo analyses confirmed that THY1+ CAFs promote oxaliplatin resistance in GC cells via extracellular vesicles (EVs). Inhibition of EV secretion reduced the chemoresistance-enhancing effects of THY1+ CAFs. Proteomic profiling of EVs identified COL11A1 as a protein enriched in THY1+ CAF-derived EVs, which was further validated by immunofluorescence and Western blot. Depletion of COL11A1 in THY1+ CAF-EVs substantially attenuated their ability to enhance drug resistance in GC cells. High infiltration of COL11A1+ and THY1+ CAFs was correlated with reduced overall survival and recurrence-free survival in GC patients. RNA sequencing and pathway analysis revealed that THY1+ CAF-EVs induce oxaliplatin resistance by activating the PI3K/AKT signaling pathway. Targeting PI3K/AKT signaling counteracted EV-induced chemoresistance, and COL11A1 knockdown in THY1+ CAF-EVs reduced PI3K/AKT activation. In conclusion, COL11A1 packaged in THY1+ CAF-derived EVs promotes GC chemoresistance via PI3K/AKT signaling, highlighting a potential therapeutic target for overcoming chemoresistance in GC.

Radiotherapy is a standard cancer treatment that involves the induction of DNA damage. DNA damage repair (DDR) pathways maintain genomic integrity and make tumors resistant to radiotherapy and certain chemotherapies. In turn, DDR dysfunction results in cumulative DNA damage, leading to increased sensitivity for antitumor treatment. Moreover, radiotherapy has been shown to trigger antitumor immunity. Currently, immunotherapy has become a new and widely used standard strategy for treating a broad spectrum of tumor types. Notably, recent studies have demonstrated that DDR pathways play important roles in driving the response to immunotherapy. Herein, we review and discuss how DDR affects antitumor immunity induced by radiotherapy. Furthermore, we summarize the development of strategies for combining DDR inhibitors with radiotherapy and/or immunotherapy to enhance their efficacy against cancers.

As a key component of the tumor microenvironment, cancer-associated fibroblasts (CAFs) exhibit substantial heterogeneity and contribute significantly to tumor growth and progression. However, their involvement in shaping the pre-metastatic niche remains insufficiently characterized. This study demonstrates that extracellular vesicles (EVs) regulated by YAP signaling in podoplanin (PDPN)⁺LTBP1⁺ CAFs activate hepatic stellate cells (HSCs), thereby enhancing gastric cancer (GC) cell colonization in the liver. Mass spectrometry profiling of EVs from PDPN⁺ and PDPN⁻ CAFs identified latent transforming growth factor beta-binding protein 1 (LTBP1) as a key mediator driving the phenotypic conversion of HSCs into CAF-educated HSCs (CEHs). Exposure to LTBP1-deficient EVs resulted in attenuated CEH-induced malignancy in HGC27 and AGS GC cells. Integrated RNA sequencing and cytokine array analyses further revealed that LTBP1-containing EVs activated TGF-β signaling in HSCs, leading to CCL11 secretion. This chemokine, in turn, recruited CCR3⁺ metastatic cells to the liver microenvironment. Using a GC liver metastasis model in combination with PET–CT imaging, inhibition of the CCL11/CCR3 axis was shown to suppress CEH-driven tumor growth and metastatic potential. These findings identify LTBP1-enriched EVs from PDPN⁺LTBP1⁺ CAFs as a viable therapeutic target to impede GC liver metastasis.

Gastric cancer (GC) remains one of the most lethal malignancies globally, with limited therapeutic options. Cancer-associated fibroblasts (CAFs), a diverse population of stromal cells within the tumor microenvironment (TME), play a central role in tumor progression and therapeutic resistance. However, the specific markers identifying tumor-promoting CAF subsets in GC have yet to be fully characterized. Through animal studies and RNA sequencing, complement C3 (C3) emerged as a key marker linked to tumor-promoting CAF subsets. Single-cell sequencing and multiplex immunofluorescence staining confirmed that C3 expression is predominantly localized within CAFs. Independent cohort analyses demonstrated a strong association between elevated levels of C3+ CAFs and poor clinical outcomes in GC patients. To further investigate, small interfering RNA (siRNA)-mediated knockdown of C3 in CAFs was employed in vitro, with subsequent experiments, including cell migration assays, cell viability assays, and immunofluorescence, revealing significant functional impacts. C3 secreted by CAFs promoted Epithelial-mesenchymal transition (EMT) and accelerated cancer cell migration. Patients with minimal C3+ CAF infiltration exhibited a higher probability of deriving therapeutic benefit from adjuvant treatments. Furthermore, C3+ CAFs were associated with immunosuppressive effects and an immune-evasive microenvironment marked by CD8 + T cell dysfunction. A lower prevalence of C3+ CAFs correlated with improved responsiveness to immunotherapy in GC patients. Enrichment analysis highlighted pronounced activation of the NF-κB signaling pathway in C3+ CAFs relative to their C3− counterparts, supported by elevated phosphorylation levels of IKK, IκBα, and p65 in C3+ CAFs compared to both C3− CAFs and normal fibroblasts (NFs). Silencing p65 nuclear translocation in CAFs through siRNA significantly suppressed C3 secretion. The study suggests that NF-κB pathway-mediated CAF activation enhances C3 secretion, driving EMT, migration, chemoresistance, and immune evasion in GC progression. Targeting the NF-κB/C3 signaling axis in CAFs may offer a viable therapeutic strategy for GC management.

Cancer-associated fibroblasts (CAFs) are heterogeneous stromal cells present in the tumor microenvironment (TME), which play a critical role in gastric cancer (GC) progression. Here, we examined a subset of CAFs with high podoplanin (PDPN) expression, which is correlated with tumor metastasis and poor survival in GC patients. Animal models of gastric cancer liver metastasis monitored by micro-PET/CT confirmed that periostin (POSTN) derived from PDPN(+) CAFs regulated CAFs' pro-migratory ability. Mechanistically, PDPN(+) CAFs secreted POSTN to modulate cancer stem cells (CSCs) through FAK/AKT phosphorylation. Furthermore, POSTN could also activate FAK/YAP signaling in GC cells to produce increased amounts of IL-6, which in turn induced phosphorylation of PI3K/AKT in PDPN(+) CAFs. Prolonged PI3K/AKT pathway activation in PDPN(+) CAFs maintains the production of POSTN and the effect on CSC enrichment and GC cell migration. In conclusion, our study demonstrated a positive feedback loop between PDPN(+) CAFs and CSCs during GC progression and suggested a selective target for GC treatment.

Radioresistance challenges the clinical outcomes of nasopharyngeal carcinoma (NPC). The 3‐phosphoinositide‐dependent protein kinase 1 (PDK1) is a crucial kinase of PI3K/AKT signaling pathway which has been implicated in the process of radioresistance. However, the role of PDK1 in NPC remains largely unclear.

Egl-9 Family Hypoxia Inducible Factor 1 (EGLN1) is a proline hydroxylase mediating degradation of hypoxia-inducible factor α (HIFα) through the ubiquitination system. Studies have indicated an essential role for EGLN1 in angiogenesis and tumorigenesis. However, there is no consensus on the regulation of EGLN1 and its mechanism of action on nasopharyngeal carcinoma (NPC). This study explored the association of the expression of EGLN1 with characteristics of NPC tumors and its underlying mechanism. We found that the expression of EGLN1 showed a positive correlation with tumor T classification and clinical staging of patients with NPC. EGLN1 could promote cell proliferation, invasion and migration, and even enhance the cancer stem cells (CSCs) prosperity and radioresistance of NPC cells. Mechanistically, EGLN1 facilitated degradation of tumor protein p53 through the ubiquitination system. This effect could be weakened in the presence of dimethyloxalylglycine (DMOG), suggesting that EGLN1 down-regulated p53 based on its hydroxylase activity. In conclusion, overexpression of EGLN1 promoted oncogenesis and induced a CSC-like phenotype in NPC cells, then enhancing the ability for radioresistance by interacting with p53 in a hydroxylase-dependent manner. Thus, EGLN1 might serve as a potential therapeutic target for NPC.

Background Fermitin family member 1 (FERMT1) is significantly overexpressed in human cancers and associated with poor prognosis, but its contributions to tumorigenesis and nasopharyngeal carcinoma (NPC) progression remain unclear. Methods The public GEO database was examined to investigate the role of FERMT1. Immunohistochemistry (IHC) staining of FERMT1 was performed in NPC tissues to corroborate the results. Western blotting and qRT-PCR were performed to test the expression of related proteins and mRNAs. Cell counting kit-8 assay (CCK8 assay) and colony formation assays were carried out to investigate the association of FERMT1 expression with NPC cell proliferation. The wound healing assay and Transwell assay were used to detect the migration and invasion of NPC cells. Flow cytometric analysis was conducted to detect the cell cycle transition of NPC cells. Co-immunoprecipitation (Co-IP) was employed to identify the correlation of FEMRT1 and Nod-like receptor family protein 3 (NLRP3). Xenograft tumors were generated to investigate the effect of FERMT1 on the growth of NPC cells in vivo. Results Here, we found that FERMT1 was upregulated in NPC tissues and correlated with the clinicopathological characteristics of NPC patients. Moreover, knockdown of FERMT1 significantly decreased cell proliferation, migration and invasion by mediating epithelial-mesenchymal transition (EMT) and cell cycle arrest of NPC cells both in vitro and in vivo. Knockdown FERMT1 inhibited EMT through directly binding to the NLRP3 and inhibited NF-kB signaling pathway. Conclusion These data indicated that FERMT1 could be a good potential therapeutic target for NPC treatment.

目的 观察培美曲塞+奈达铂联合贝伐珠单抗治疗后培美曲塞联合贝伐珠单抗维持治疗方案在晚期非鳞非小细胞肺癌患者中的疗效和安全性,并探讨影响该化疗方案疗效的相关因素.方法 收集2015年6月—2018年6月经病理确诊的50例晚期非鳞非小细胞肺癌患者,所有患者均接受培美曲塞+奈达铂联合贝伐珠单抗治疗,并对治疗后疾病未进展的患者给予培美曲塞联合贝伐珠单抗维持治疗,直至疾病进展或出现不可耐受的不良反应.对患者的近期疗效和不良反应进行分析.结果 50例患者的客观缓解率(ORR)和疾病控制率(DCR)分别为42％(21/50)和86％(43/50),中位无进展生存期(PFS)为11个月(95％CI:8.1～13.9).治疗相关不良反应主要为骨髓抑制,但均可耐受,无不良反应相关性死亡.结论 培美曲塞+奈达铂联合贝伐珠单抗治疗后培美曲塞联合贝伐珠单抗维持化疗方案在晚期非鳞非小细胞肺癌患者中有较好的疗效和安全性.

DNA damage repair plays an important role in cancer’s initiation and progression, and in therapeutic resistance. The prognostic potential of damage repair indicators was studied in the case of clear cell renal cell carcinoma (ccRCC). Gene expression profiles of the disease were downloaded from cancer genome databases and gene ontology was applied to the DNA repair-related genes. Twenty-six differentially expressed DNA repair genes were identified, and regression analysis was used to identify those with prognostic potential and to construct a risk model. The model accurately predicted patient outcomes and distinguished among patients with different expression levels of immune evasion genes. The data indicate that DNA repair genes can be valuable for predicting the progression of clear cell renal cell carcinoma and the clinical benefits of immunotherapy.

Riluzole is approved by the FDA as an amyotrophic lateral sclerosis (ALS) drug. Previous studies showed that treatment with riluzole suppressed the proliferation of many cancer cells. However, little is known about its effects on nasopharyngeal carcinoma (NPC) and its molecular mode of action. In this study, we determined the effect of riluzole on apoptosis, cell cycle, migration, and invasion in NPC cell lines and investigated its mechanism at the molecular level. By using the human NPC cell lines CNE1, CNE2, and HNE1, we revealed that riluzole effectively inhibited viability of the NPC cell lines in dose- and time-dependent manners. Furthermore, riluzole dose-dependently induced apoptosis and G2/M cell cycle arrest in the NPC cell lines. After combination with radiotherapy (RT), greater cytotoxicity was achieved than with riluzole or RT alone in vitro and vivo. This was associated with the activation of ataxia telangiectasia mutated (ATM) and phosphoinositide p53 pathways. P53 silencing reduced cell reactiveness to riluzole therapy. These observations demonstrate that the riluzole-activated ATM/P53 pathway is directly involved in radiation-induced apoptosis of NPC cells. Given the acceptable side effect, combining of riluzole and radiotherapy is promising in NPC treatment.

Radiotherapy with or without concurrent chemotherapy is the standard treatment for nasopharyngeal carcinoma (NPC) patients, whose efficacy is limited partly by intrinsic and acquired radioresistance. DNA methyltransferase 3B (DNMT3B) has been reported to participate in tumorigenesis via DNA methylation, but its role in mediating progression and radioresistance of NPC remains unclear. Therefore, we conducted the following studies to explore the relationship between DNMT3B and NPC. Here, we found that DNMT3B was elevated in NPC tissues and predicted the poor prognosis of NPC patients. We demonstrated for the first time that ionizing radiation could induce DNMT3B, which might be one of the reasons for radioresistance. Silencing of DNMT3B inhibited migration and invasion via suppressing epithelial-mesenchymal transition (EMT) in NPC cells. Furthermore, silencing DNMT3B restored and activated p53 and p21 via DNA demethylation, which led to cell cycle arrest and apoptosis, resulting in increased radiosensitivity of NPC both in vitro and in vivo. DNMT3B functions as a novel oncogene in the radioresistance of NPC through regulating EMT, cell cycle, and apoptosis. Therefore, DNMT3B could be a potential target for NPC treatment.

Radiotherapy is the mainstay and primary curative treatment modality in nasopharyngeal carcinoma (NPC), whose efficacy is limited by the development of intrinsic and acquired radioresistance. Thus, deciphering new molecular targets and pathways is essential for enhancing the radiosensitivity of NPC. SALL4 is a vital factor in the development and prognosis of various cancers, but its role in radioresistance remains elusive. This study aimed to explore the association of SALL4 expression with radioresistance of NPC. It was revealed that SALL4 expression was closely correlated with advanced T classification of NPC patients. Inhibition of SALL4 reduced proliferation and sensitized cells to radiation both in vitro and in vivo. Furthermore, SALL4 silencing increased radiation-induced DNA damage, apoptosis, and G2/M arrest in CNE2 and CNE2R cells. Moreover, knockdown of SALL4 impaired the expression of p-ATM, p-Chk2, p-p53, and anti-apoptosis protein Bcl-2, while pro-apoptosis protein was upregulated. These findings indicate that SALL4 could induce radioresistance via ATM/Chk2/p53 pathway and its downstream proteins related to apoptosis. Targeting SALL4 might be a promising approach for the development of novel radiosensitizing therapeutic agents for radioresistant NPC patients.

Mutations in the forkhead box O 3a (FOXO3a) gene are closely related to the progression of several types of cancers. However, few studies explore the relationship between FOXO3a and nasopharyngeal carcinoma (NPC). Our findings demonstrate that silencing FOXO3a promotes tumor radioresistance of NPC in vitro and in vivo through inducing EMT and activating Wnt/β-catenin signal pathway. These data establish that FOXO3a can be a novel and reliable NPC marker and a potential therapeutic target against NPC.

Malnutrition is a common problem in patients with nasopharyngeal carcinoma (NPC), a highly prevalent cancer in southern China, which exerts adverse impacts on the quality of life, therapeutic effectiveness, and thus the prognosis of patients. It has been elucidated that malnutrition in patients with NPC is mainly attributed to systemic inflammation provoked by proinflammatory cyto-kines produced by the tumor, which elicits abnormal neuroendocrine and metabolic changes that ensue. The adverse effects of thera-peutic interventions for NPC and psychological factors also play ceritical roles. Early risk screening and diagnosis of malnutrition is the prerequisite for effective intervention, which should include comprehensive measures ranging from nutritional counseling and pain control, as well as anabolic stimulating exercises. In this paper, with reference to recently published studies and clinical guidelines, the nutritional status of patients with NPC and the progress of nutritional interventions are discussed.