HLA diversity unveils susceptibility and organ-specific occurrence of second primary cancers: a prospective cohort study.

BACKGROUND: Up to 17% of cancer survivors have been reported to develop second primary cancers (SPC), which cause significant physical and economic distress and often complicate clinical decision-making. However, understanding of SPC remains limited and superficial. Human leukocyte antigen (HLA) is characterized by its polymorphism and has been associated with various diseases. This study aims to explore the role of HLA diversity in SPC incidence. METHODS: We analyzed a cohort of 47,550 cancer patients from the UK Biobank. SNP-derived HLA alleles were used and SPC-related HLA alleles were identified using logistic regression, followed by stepwise filtering based on the Akaike information criterion (AIC) and permutation tests. Additionally, we examined the association between extragenetic factors and the risk of SPC in patients carrying hazardous HLA alleles. RESULTS: During a median follow-up of 3.11 years, a total of 2894 (6.09%) participants developed SPC. We identified three protective HLA alleles (DRB1*04:03 and DPA1*02:02 for males and DRB5*01:01 for females) and two hazardous alleles (A*26:01 for males and DPB1*11:01 for females) about SPC. The presence of the protective alleles was associated with a reduced SPC risk (males: hazard ratio [HR] 0.72, 95% confidence interval [CI] 0.59-0.89; females: HR 0.81, 95% CI 0.70-0.93), while the hazardous alleles were linked to an increased risk (males: HR 1.27, 95% CI 1.03-1.56; females: HR 1.35, 95% CI 1.07-1.70). The hazardous allele A*26:01 indicated skin-lung organ-specific SPC occurrence in males. Animal fat and vitamin C were associated with SPC risk in males carrying the hazardous alleles, while free sugar and vegetable fat were linked to SPC risk in females. CONCLUSIONS: These results suggest that HLA alleles may serve as biomarkers for the susceptibility and organ-specific occurrence of SPC, while dietary modulation may mitigate hazardous alleles-related SPC risk, potentially aiding in the early prediction and prevention of SPC.

Immunological challenges and opportunities in glioblastoma multiforme: A comprehensive view from immune system lens.

Glioblastoma multiforme (GBM), also known as grade IV astrocytoma, is the most common and deadly brain tumour. It has a poor prognosis and a low survival rate. GBM cells' immunological escape mechanism helps them resist advanced multimodal therapy. In physiological homeostasis, brain astrocytes and microglia suppress infections and clear the potential pathogen from the system. However, in severe pathological conditions like cancer, the immune response fails to eliminate mutated and rapidly over-proliferating GBM cells. The malignant cells' interactions with immune cells and the neoplasm's immunosuppressive environment enable the avoidance and their clearance. Immunotherapy efficiently addresses these difficulties, as shown by sufficient evidence. This review discusses how GBM cells inhibit and elude the immune system. These include MHC molecule expression alteration and PD-L1 and CTLA-4 immune checkpoint overexpression. Without co-stimulation, these changes induce effector T-cell tolerance and anergy. The review also covers how MDSCs, TAMs, Herpes Virus Entry Mediators, and Human cytomegalovirus protein decrease the effector immune response against glioblastoma. The latter part discusses various therapies that are available in the market or under clinical trials which revolves around combating resistance against the available multimodal therapies. The recent trends indicate that there are various monoclonal antibodies and peptide-based vaccines that can be utilized to overcome the immune evasion technique harbored by GBM cells. A strategic development of Immunotherapy considering these hallmarks of immune evasion may help in designing a therapy that may prove to be effective in killing the GBM cells thereby, improving the overall survival of GBM-affected patients.

Neudesin regulates dendritic cell function and antitumor CD8+ T cell immunity.

Dendritic cells (DCs) are essential for antitumor T-cell responses to immune checkpoint inhibitor therapies. We have previously reported that the secreted protein neudesin suppresses DC function. In contrast, neudesin has been found to be abundantly expressed in human cancers. In this study, we evaluated the role of neudesin in cancer immunity. Cancer-related database analysis revealed that patients with melanoma with low neudesin expression exhibited increased infiltration of DCs and CD8+ T cells and improved outcomes of checkpoint inhibitor therapy. In mouse tumor models, neudesin deficiency delayed tumor growth and increased the proportions of Type 1 conventional DCs (cDC1s) and tumor antigen-specific CD8+ T cells in tumors and tumor-infiltrating lymph nodes. Neudesin-deficient antitumor cDC1 vaccine enhanced the systemic immunity more effectively than the wild-type cDC1 vaccine. Overall, our findings highlight the importance of neudesin in cancer immunity, providing a novel target for immunotherapy.

S. glabra exerts anti-lung cancer effects by inducing ferroptosis and anticancer immunity.

BACKGROUND: Sarcandra glabra (S. glabra), a traditional Chinese medicine (TCM), has demonstrated significant anticancer activity; however, the underlying mechanisms have not yet been fully elucidated. PURPOSE: This study aimed to investigate the effects of S. glabra on lung cancer and to explore its underlying mechanisms. METHODS: The chemical profile of S. glabra was analyzed via ultrahigh-performance liquid chromatography coupled with mass spectrometry (UPLC-MS). The effects of S. glabra on the viability, proliferation, apoptosis, migration, and invasion of lung cancer cells were assessed via CCK8, colony formation, flow cytometry, scratch, and Transwell assays. In vivo anticancer activity was evaluated in an LLC mouse model. Proteomic analysis was performed to identify key molecules and pathways in S. glabra-treated LLC cells. The expression of ferroptotic proteins and associated cellular events were examined via western blotting, ROS production, iron accumulation, and lipid peroxidation assays. Immune modulation in tumor-bearing mice was evaluated by detecting immune cells and cytokines in the peripheral blood and tumor tissue. RESULTS: Our analysis quantified 1997 chemical markers in S. glabra aqueous extracts. S. glabra inhibited the viability and proliferation of lung cancer cells and induced cell cycle arrest and apoptosis. Scratch and Transwell assays demonstrated that S. glabra suppressed the migration and invasion of lung cancer cells. Oral administration of S. glabra significantly inhibited tumor growth in LLC tumor-bearing mice. Proteomic analysis revealed that S. glabra upregulated the expression of the HMOX1 protein and activated the ferroptosis pathway. Consistent with these findings, we found that S. glabra triggered ferroptosis in lung cancer cells, as evidenced by the upregulation of HMOX1, downregulation of GPX4 and ferritin light chain proteins, iron accumulation, increased ROS production, and lipid peroxidation. Furthermore, S. glabra demonstrated immunostimulatory properties in LLC tumor-bearing mice, leading to increased populations of immune cells (NK cells) and elevated cytokine levels (IL-2). CONCLUSION: This study is the first to demonstrate that S. glabra induces ferroptosis in lung cancer cells by regulating HMOX1, GPX4, and FTL. These findings provide a robust scientific basis for the clinical application of S. glabra in lung cancer treatment.

Impact of exercise on cancer: mechanistic perspectives and new insights.

This review critically evaluates the substantial role of exercise in enhancing cancer prevention, treatment, and patient quality of life. It conclusively demonstrates that regular physical activity not only reduces cancer risk but also significantly mitigates side effects of cancer therapies. The key findings include notable improvements in fatigue management, reduction of cachexia symptoms, and enhancement of cognitive functions. Importantly, the review elucidates the profound impact of exercise on tumor behavior, modulation of immune responses, and optimization of metabolic pathways, advocating for the integration of exercise into standard oncological care protocols. This refined abstract encourages further exploration and application of exercise as a pivotal element of cancer management.

Is End-Stage Renal Disease Tumor Suppressive? Dispelling the Myths.

The prevalence of end-stage renal disease is increasing worldwide. Malignancies accompanying end-stage renal disease are detected in approximately 120 individuals per 10,000 person-years. Most studies have suggested that end-stage renal disease causes carcinogenesis and promotes tumor development; however, this theory remains questionable. Contrary to the theory that end-stage renal disease is predominantly carcinogenic, recent findings have suggested that after controlling for biases and sampling errors, the overall cancer risk in patients with end-stage renal disease might be lower than that in the general population, except for renal and urothelial cancer risks. Additionally, mortality rates associated with most cancers are lower in patients with end-stage renal disease than in the general population. Several biological mechanisms have been proposed to explain the anticancer effects of end-stage renal disease, including premature aging and senescence, enhanced cancer immunity, uremic tumoricidal effects, hormonal and metabolic changes, and dialysis therapy-related factors. Despite common beliefs that end-stage renal disease exacerbates cancer risk, emerging evidence suggests potential tumor-suppressive effects. This review highlights the potential anticancer effects of end-stage renal disease, proposing reconsideration of the hypothesis that end-stage renal disease promotes cancer development and progression.

Targeting hepcidin in colorectal cancer triggers a TNF-dependent-gasdermin E-driven immunogenic cell death response.

Interactions between colorectal cancer (CRC) cells and the noncancerous cells in the tumor microenvironment (TME) induce mechanisms for the escape of tumor cells from immune attack. Hepcidin, a peptide that controls immune cell functions, is overproduced by CRC cells. This study aimed to evaluate whether hepcidin acts as a regulator of anti-tumor immunity in CRC. Hepcidin silencing in CRC cells was followed by enhanced TNF-driven caspase-dependent cleavage of GSDM E and death. Mice engrafted with hepcidin-deficient CT26 cells developed fewer and smaller tumors than control mice as a result of the action of tumor-infiltrating CD8+ T lymphocytes and were protected from the development of tumors in a vaccination model and exhibited long-lasting tumor protection. Additionally, hepcidin deficiency enhanced the response of mice bearing CT26-derived tumors to anti-PD-1 therapy. These results suggest that targeting hepcidin in CRC cells enhances the production of TNF thereby triggering a caspase/GSDM E-driven lytic cell death with the downstream effect of boosting a robust immune response against tumor antigens.

Host ANGPTL2 establishes an immunosuppressive tumor microenvironment and resistance to immune checkpoint therapy.

Use of immune checkpoint inhibitors (ICIs) as cancer immunotherapy has advanced rapidly in the clinic; however, mechanisms underlying resistance to ICI therapy, including impaired T cell infiltration, low immunogenicity, and tumor "immunophenotypes" governed by the host, remain unclear. We previously reported that in some cancer contexts, tumor cell-derived angiopoietin-like protein 2 (ANGPTL2) has tumor-promoting functions. Here, we asked whether ANGPTL2 deficiency could enhance antitumor ICI activity in two inflammatory contexts: a murine syngeneic model of colorectal cancer and a mouse model of high-fat diet (HFD)-induced obesity. Systemic ANGPTL2 deficiency potentiated ICI efficacy in the syngeneic model, supporting an immunosuppressive role for host ANGPTL2. Relevant to the mechanism, we found that ANGPTL2 induces pro-inflammatory cytokine production in adipose tissues, driving generation of myeloid-derived suppressor cells (MDSCs) in bone marrow and contributing to an immunosuppressive tumor microenvironment and resistance to ICI therapy. Moreover, HFD-induced obese mice showed impaired responsiveness to ICI treatment, suggesting that obesity-induced chronic inflammation facilitated by high ANGPTL2 expression blocks ICI antitumor effects. Our findings overall provide novel insight into protumor ANGPTL2 functions and illustrate the essential role of the host system in ICI responsiveness.

Spatiotemporal metabolomic approaches to the cancer-immunity panorama: a methodological perspective.

Metabolic reprogramming drives the development of an immunosuppressive tumor microenvironment (TME) through various pathways, contributing to cancer progression and reducing the effectiveness of anticancer immunotherapy. However, our understanding of the metabolic landscape within the tumor-immune context has been limited by conventional metabolic measurements, which have not provided comprehensive insights into the spatiotemporal heterogeneity of metabolism within TME. The emergence of single-cell, spatial, and in vivo metabolomic technologies has now enabled detailed and unbiased analysis, revealing unprecedented spatiotemporal heterogeneity that is particularly valuable in the field of cancer immunology. This review summarizes the methodologies of metabolomics and metabolic regulomics that can be applied to the study of cancer-immunity across single-cell, spatial, and in vivo dimensions, and systematically assesses their benefits and limitations.

Insights into therapeutic peptides in the cancer-immunity cycle: Update and challenges.

Immunotherapies hold immense potential for achieving durable potency and long-term survival opportunities in cancer therapy. As vital biological mediators, peptides with high tissue penetration and superior selectivity offer significant promise for enhancing cancer immunotherapies (CITs). However, physicochemical peptide features such as conformation and stability pose challenges to their on-target efficacy. This review provides a comprehensive overview of recent advancements in therapeutic peptides targeting key steps of the cancer-immunity cycle (CIC), including tumor antigen presentation, immune cell regulation, and immune checkpoint signaling. Particular attention is given to the opportunities and challenges associated with these peptides in boosting CIC within the context of clinical progress. Furthermore, possible future developments in this field are also discussed to provide insights into emerging CITs with robust efficacy and safety profiles.

Recapitulating the Cancer-Immunity Cycle on a Chip.

The cancer-immunity cycle is a fundamental framework for understanding how the immune system interacts with cancer cells, balancing T cell recognition and elimination of tumors while avoiding autoimmune reactions. Despite advancements in immunotherapy, there remains a critical need to dissect each phase of the cycle, particularly the interactions among the tumor, vasculature, and immune system within the tumor microenvironment (TME). Innovative platforms such as organ-on-a-chip, organoids, and bioprinting within microphysiological systems (MPS) are increasingly utilized to enhance the understanding of these interactions. These systems meticulously replicate crucial aspects of the TME and immune responses, providing robust platforms to study cancer progression, immune evasion, and therapeutic interventions with greater physiological relevance. This review explores the latest advancements in MPS technologies for modeling various stages of the cancer-immune cycle, critically evaluating their applications and limitations in advancing the understanding of cancer-immune dynamics and guiding the development of next-generation immunotherapeutic strategies.

Spontaneous Resolution of Abdominal Pseudohernia Following Lung Cancer Surgery: A Case Report.

Abdominal pseudohernia is a condition characterized by the protrusion of abdominal viscera through a weakened area of the abdominal wall without a hernia sac. Various causes, including spinal disorders and trauma, can lead to this condition; however, the most common cause is reported to be herpes zoster. We present a rare case of spontaneous resolution of abdominal pseudohernia following lung cancer surgery. A 71-year-old male presented with left upper abdominal bulging and pain. A CT scan performed at the time incidentally revealed a nodular lesion in the right lower lobe, suspicious for lung cancer. Single-port thoracoscopic surgery was performed, and the final diagnosis was right lower lobe lung squamous cell carcinoma. Following the lung cancer surgery, the left upper abdominal bulging spontaneously resolved within one week. In this case, we hypothesize that the immune dysregulation caused by lung cancer increased the activity of the herpes zoster virus, leading to the development of pseudohernia. The spontaneous resolution of the pseudohernia is thought to be due to the improvement of immune dysregulation after surgery.

Establishment of a chemokine-based prognostic model and identification of CXCL10+ M1 macrophages as predictors of neoadjuvant therapy efficacy in colorectal cancer.

Background: Although neoadjuvant therapy has brought numerous benefits to patients, not all patients can benefit from it. Chemokines play a crucial role in the tumor microenvironment and are closely associated with the prognosis and treatment of colorectal cancer. Therefore, constructing a prognostic model based on chemokines will help risk stratification and providing a reference for the personalized treatment. Methods: Employing LASSO-Cox predictive modeling, a chemokine-based prognostic model was formulated, harnessing the data from TCGA and GEO databases. Then, our exploration focused on the correlation between the chemokine signature and elements such as the immune landscape, somatic mutations, copy number variations, and drug sensitivity. CXCL10+M1 macrophages identified via scRNA-seq. Monocle2 showed cell pseudotime trajectories, CellChat characterized intercellular communication. CytoTRACE analyzed neoadjuvant therapy stemness, SCENIC detected cell type-specific regulation. Lastly, validation was performed through multiplex immunofluorescence experiments. Results: A model based on 15 chemokines was constructed and validated. High-risk scores correlated with poorer prognosis and advanced TNM and clinical stages. Individuals presenting elevated risk scores demonstrated an increased propensity towards the development of chemotherapy resistance. Subsequent scRNA-seq data analysis indicated that patients with higher presence of CXCL10+ M1 macrophages in tumor tissues are more likely to benefit from neoadjuvant therapy. Conclusion: We developed a chemokine-based prognostic model by integrating both single-cell and bulk RNA-seq data. Furthermore, we revealed epithelial cell heterogeneity in neoadjuvant outcomes and identified CXCL10+ M1 macrophages as potential therapy response predictors. These findings could significantly contribute to risk stratification and serve as a key guide for the advancement of personalized therapeutic approaches.

MiR-223-3p in Cancer Development and Cancer Drug Resistance: Same Coin, Different Faces.

MicroRNAs (miRNAs) are mighty post-transcriptional regulators in cell physiology and pathophysiology. In this review, we focus on the role of miR-223-3p (henceforth miR-223) in various cancer types. MiR-223 has established roles in hematopoiesis, inflammation, and most cancers, where it can act as either an oncogenic or oncosuppressive miRNA, depending on specific molecular landscapes. MiR-223 has also been linked to either the sensitivity or resistance of cancer cells to treatments in a context-dependent way. Through this detailed review, we highlight that for some cancers (i.e., breast, non-small cell lung carcinoma, and glioblastoma), the oncosuppressive role of miR-223 is consistently reported in the literature, while for others (i.e., colorectal, ovarian, and pancreatic cancers, and acute lymphocytic leukemia), an oncogenic role prevails. In prostate cancer and other hematological malignancies, although an oncosuppressive role is frequently described, there is less of a consensus. Intriguingly, NLRP3 and FBXW7 are consistently identified as miR-223 targets when the miRNA acts as an oncosuppressor or an oncogene, respectively, in different cancers. Our review also describes that miR-223 was increased in biological fluids or their extracellular vesicles in most of the cancers analyzed, as compared to healthy or lower-risk conditions, confirming the potential application of this miRNA as a diagnostic and prognostic biomarker in the clinic.

Macrophage-mediated myelin recycling fuels brain cancer malignancy.

Tumors growing in metabolically challenged environments, such as glioblastoma in the brain, are particularly reliant on crosstalk with their tumor microenvironment (TME) to satisfy their high energetic needs. To study the intricacies of this metabolic interplay, we interrogated the heterogeneity of the glioblastoma TME using single-cell and multi-omics analyses and identified metabolically rewired tumor-associated macrophage (TAM) subpopulations with pro-tumorigenic properties. These TAM subsets, termed lipid-laden macrophages (LLMs) to reflect their cholesterol accumulation, are epigenetically rewired, display immunosuppressive features, and are enriched in the aggressive mesenchymal glioblastoma subtype. Engulfment of cholesterol-rich myelin debris endows subsets of TAMs to acquire an LLM phenotype. Subsequently, LLMs directly transfer myelin-derived lipids to cancer cells in an LXR/Abca1-dependent manner, thereby fueling the heightened metabolic demands of mesenchymal glioblastoma. Our work provides an in-depth understanding of the immune-metabolic interplay during glioblastoma progression, thereby laying a framework to unveil targetable metabolic vulnerabilities in glioblastoma.

Pan-cancer bioinformatics analysis of hepatic leukemia factor and further validation in colorectal cancer.

Background: Hepatic leukemia factor (HLF) is associated with cancer onset, growth, and progression; however, little is known regarding its biological role in pan-cancer. In order to further evaluate the diagnostic and prognostic value of HLF in pan-cancer and colorectal cancer (CRC), we performed comprehensive bioinformatics analyses of the molecular mechanism of HLF in pan-cancer, with subsequent verification in CRC. Methods: We downloaded data (gene expression, clinical data, follow-up duration, and immune-related data) related to 33 solid tumor types from UCSC Xena (University of California Santa Cruz cancer database, https://xena.ucsc.edu/). HLF expression was analyzed in pan-cancer, and its diagnostic efficacy, prognostic value, and correlation with pathological stage and cancer immunity were determined. We also analyzed gene alterations in HLF and biological processes involved in its regulation in pan-cancer. Using CRC data in The Cancer Genome Atlas (TCGA), we assessed correlations between HLF and CRC diagnosis, prognosis, and drug sensitivity and performed functional enrichment analyses. Moreover, we constructed an HLF-related ceRNA regulatory network. Finally, we externally validated HLF expression and diagnostic and prognostic value in CRC using Gene Expression Omnibus (GEO) database, as well as by performing in vitro experiments. Results: HLF expression was downregulated in most tumors, and HLF showed good predictive potential for pan-cancer diagnosis and prognosis. It was closely related to the clinicopathological stages of pan-cancer. Further, HLF was associated with tumor microenvironment and immune cell infiltration in many tumors. Analyses involving cBioPortal revealed changes in HLF amplifications and mutations in most tumors. HLF was also closely associated with microsatellite instability and tumor mutational burden in pan-cancer and involved in regulating various tumor-related pathways and biological processes. In CRC, HLF expression was similarly downregulated, with implications for CRC diagnosis and prognosis. Functional enrichment analysis indicated the association of HLF with many cancer-related pathways. Further, HLF was associated with drug (e.g., oxaliplatin) sensitivity in CRC. The ceRNA regulatory network showed multigene regulation of HLF in CRC. External validation involving GEO databases and quantitative real-time polymerase chain reaction (qRT-PCR) data substantiated these findings. Conclusions: HLF expression generally exhibited downregulation in pan-cancer, contributing to tumor occurrence and development by regulating various biological processes and affecting tumor immune characteristics. HLF was also closely related to CRC occurrence and development. We believe HLF can serve as a reliable diagnostic, prognostic, and immune biomarker for pan-cancer.

A comprehensive prognostic and immune infiltration analysis of UBA1 in pan-cancer: A computational analysis and in vitro experiments.

Ubiquitin like modifier activating enzyme 1 (UBA1) plays an important role in immune regulation and cellular function. However, the functional mechanism and role of UBA1 in pan-cancer have not been fully elucidated and its value in haematological tumours (diffuse large B cell lymphoma (DLBC/DLBCL) and acute myeloid leukaemia (AML/LAML)) has not been explored. We conducted a comprehensive analysis of the functional mechanism and role of UBA1 in pan-cancer using multiple databases, including differential expression analysis, clinical pathological staging analysis, prognosis analysis and immune analysis. Then, we confirmed the function of UBA1 in haematological tumours through cell experiments. The results showed that the expression of UBA1 was significantly increased in most cancers and the differential expression of UBA1 was mainly concentrated in digestive tumours, haematological tumours and brain tumours. Moreover, the high expression of UBA1 had poor prognosis in most tumours, which may be related to its involvement in various cancer-related pathways such as cell cycle, as well as its methylation level, protein phosphorylation level, immune cell infiltration and immune therapy response. Cell experiments have confirmed that UBA1 can significantly regulate the cycle progression and apoptosis of DLBCL cells and AML cells. Therefore, UBA1 may be a potential therapeutic target for haematological tumours. In summary, our study not only comprehensively analysed the functional mechanisms and clinical value of UBA1 in pan-cancer, but also validated for the first time the regulatory role of UBA1 in haematological tumours.

An investigator-initiated clinical study in patients with refractory or recurrent solid tumors: 'R-ISV-FOLactis' trial.

Aim: In situ vaccination, a kind of therapeutic cancer vaccine, can be realized by radiotherapy and intratumoral immune injection. This study combines intratumoral injection, radiotherapy and PD-1 blockade for synergistic antitumor effect.Materials & methods: Patients with advanced solid tumors who are unresponsive or intolerant to standard treatment will be treated with hypofractionated radiotherapy, intratumoral injection of FOLactis, PD-1 blockade. The primary end point is to observe the efficacy and safety, with the secondary end point to evaluate abscopal effects and the correlation between the immunological rationale and efficacy.Discussion: The combined regimen will be utilized to trigger antitumor immunity and is expected to be feasible and effective and provide a novel option for the comprehensive treatment of cancer.Clinical Trial Registration: ChiCTR2200060660 (ChiCTR.gov.cn).

[Box: see text].

Targeting LSD1 in cancer: Molecular elucidation and recent advances.

Histones are the main components of chromatin, functioning as an instructive scaffold to maintain chromosome structure and regulate gene expression. The dysregulation of histone modification is associated with various pathological processes, especially cancer initiation and development, and histone methylation plays a critical role. However, the specific mechanisms and potential therapeutic targets of histone methylation in cancer are not elucidated. Lys-specific demethylase 1A (LSD1) was the first identified demethylase that specifically removes methyl groups from histone 3 at lysine 4 or lysine 9, acting as a repressor or activator of gene expression. Recent studies have shown that LSD1 promotes cancer progression in multiple epigenetic regulation or non-epigenetic manners. Notably, LSD1 dysfunction is correlated with repressive cancer immunity. Many LSD1 inhibitors have been developed and clinical trials are exploring their efficacy in monotherapy, or combined with other therapies. In this review, we summarize the oncogenic mechanisms of LSD1 and the current applications of LSD1 inhibitors. We highlight that LSD1 is a promising target for cancer treatment. This review will provide the latest theoretical references for further understanding the research progress of oncology and epigenetics, deepening the updated appreciation of epigenetics in cancer.

Current findings on the antitumor effects of metformin on esophageal squamous cell carcinoma (Review).

Esophageal squamous cell carcinoma (ESCC) is an intractable type of cancer that requires novel therapeutic modalities, since the therapeutic outcomes are often inadequate, even in response to multidisciplinary treatment. The antitumor effect of metformin, an antidiabetic drug, has been reported in esophageal cancer; however, its effects are diverse. Since various multidisciplinary therapies are used in ESCC, the antitumor effect of metformin is expected to be synergistic in some treatment strategies. The present review summarizes the antitumor effects of metformin and discusses its use in combination with existing therapies. The present study reviewed relevant studies where the molecular targets of metformin (AMPK and inflammatory system signals) were described, followed by the classification and organization of its antitumor effects, and subsequently summarized the current research on its antitumor effects, especially in ESCC. A number of studies have reported that metformin prevents the development of ESCC and exerts its antitumor effects through various pathways. In addition, metformin has been shown to inhibit tumor growth, induce apoptosis, inhibit cancer cell invasion, migration and angiogenesis into the tumor, and decrease tumor malignancy, such as metastasis. Furthermore, it may modulate host tumor immunity in a tumor-suppressive manner and is expected to improve prognosis following treatment for ESCC. Notably, metformin may be beneficial in combination with chemotherapy, such as cisplatin, and radiation. By contrast, it has been shown to potentially induce resistance to 5-fluorouracil. Finally, the effects of metformin in combination with other therapies are discussed in the present study, and perspectives on the potential benefits of metformin for future ESCC treatment are presented. In conclusion, the present review may be useful in improving the understanding of the wide range of antitumor effects of metformin. Although some concerning points remain, using metformin in ESCC treatment could be promising. Notably, more knowledge needs to be accumulated regarding the effects of metformin on ESCC.