Inflammatory bowel disease (IBD), sepsis, and intestinal tumors are major health threats. This study aimed to explore the regulatory role of CD177+ neutrophils in the BMP signaling pathway and its impact on the onset, progression, and treatment of these diseases.

Gene expression data from the Gene Expression Omnibus (GEO) database for IBD and sepsis were retrieved. Bioinformatics methods like background correction, normalization, and differential expression analysis were used. Weighted gene co-expression network analysis (WGCNA), gene functional enrichment analysis, pan-cancer analysis, single-cell analysis, and in vitro experiments including Caco-2 cell culture, cell proliferation assay (CCK-8), flow cytometry apoptosis analysis, quantitative real-time PCR (qRT-PCR), and plate colony formation assay were performed.

Key genes associated with IBD and sepsis, such as BMP2, BMP4, BMP6, BMP8A, and CD177, were identified. WGCNA in sepsis found two significant modules related to key clinical outcomes. Core gene screening revealed seven shared genes between IBD and sepsis, and enrichment analysis showed involvement in important biological processes and pathways. Pan-cancer analysis showed diverse gene expression patterns and correlations with immune dynamics. Single-cell transcriptomics provided insights into the tumor microenvironment. In vitro experiments demonstrated that CD177 knockdown affected BMP signaling pathway-related gene expression, ROS production, apoptosis, and cell proliferation.

CD177+ neutrophils play a crucial role in regulating the BMP signaling pathway in IBD, sepsis, and intestinal tumors. These findings offer potential therapeutic targets, but further clinical validation is required to translate them into effective treatment strategies.

Tumor-associated neutrophils (TANs) play crucial roles in tumor progression, immune response modulation, and the therapeutic outcomes. Despite significant advancements in TAN research, a comprehensive bibliometric analysis that objectively presents the current status and trends in this field is lacking. This study aims to fill this gap by visually analyzing global trends in TANs research using bibliometric and knowledge mapping techniques.

We retrieved articles and reviews related to TANs from the Web of Science core collection database, spanning the period from 2012 to2024. The data was analyzed using bibliometric tools such as Excel 365, CiteSpace, VOSviewer, and Bibliometrix (R-Tool of R-Studio) to identify key trends, influential countries and institutions, collaborative networks. and citation patterns.

A total of 6l5 publications were included in the bibliometric analysis, showing a significant upward trend in TANs research over the last two decades. The United States and China emerged as the leading contributors with the highest number of publications and citations. The journal with the most publications in this field is Frontiers in Immunology, Prominent authors such as Fridlender ZG was identified as the key contributor, with his works frequently cited. The analysis highlighted major research themes. including the role of TANs in tumor microenvironment modulation, their dual functions in tumor promotion and suppression, and the exploration of TANs-targeted therapies, Emerging research hotspots include studies on TANs plasticity and their interactions with other immune cells.

This study is the first to employ bibliometric methods to visualize trends and frontiers in TANs research. The findings provide valuable insights into the evolution of the field, highlighting critical areas for future investigation and potential collaborative opportunities. This comprehensive analysis serves as a crucial resource for researchers and practitioners aiming to advance TAN research and its application in cancer therapy.

Neutrophil extracellular traps (NETs) participate in both host defense and the pathogenesis of various diseases, such as infections, thrombosis, and tumors. While they help capture and eliminate pathogens, NETs' excessive or dysregulated formation can lead to tissue damage and disease progression. Therapeutic strategies targeting NET modulation have shown potential, but challenges remain, particularly in achieving precise drug delivery and maintaining drug stability. Nanoparticle (NP)-based drug delivery systems offer innovative solutions for overcoming the limitations of conventional therapies. This review explores the biological mechanisms of NET formation, their interactions with NPs, and the therapeutic applications of NP-based drug delivery systems for modulating NETs. We discuss how NPs can be designed to either promote or inhibit NET formation and provide a comprehensive analysis of their potential in treating NET-related diseases. Additionally, we address the current challenges and future prospects for NP-based therapies in NET research, aiming to bridge the gap between nanotechnology and NET modulation for the development of novel therapeutic approaches.

Bacteria engineered to express tumor antigens as a cancer vaccine have yielded mixed results. Here, we utilized an attenuated strain of Listeria monocytogenes ( ΔactA, Lm ) that does not express tumor antigen to explore the immunological response to Listeria itself in the context of intravenous (IV), intratumoral (IT), or a combination of IV+IT administration into tumor-bearing mice. Unexpectedly, we found that Lm persisted in tumors of immune competent mice, regardless of the administration route. While IT Lm alone led to the recruitment of immunosuppressive immune cells that promoted tumor growth, IV Lm followed by IT Lm controlled tumor growth. IV Lm vaccination generated a pool of anti- Lm cytotoxic CD8 T cells that killed Lm -infected non-tumor cells to control tumor growth both indirectly, by limiting cancer cell proliferation, and directly, by enhancing tumor-specific T cell responses. Our findings reveal a differential impact of IT Lm administration on tumor progression that depends on the presence of anti- Lm CD8 T cells, which alone are sufficient to promote therapeutic efficacy.

Neutrophils, traditionally considered as non-specific components of the innate immune system, have garnered considerable research interest due to their dual roles in both promoting and inhibiting tumor progression. This paper seeks to clarify the specific mechanisms by which neutrophils play a bidirectional role in tumor immunity and the factors that influence these roles. By conducting a comprehensive analysis and synthesis of a vast array of relevant literature, it has become evident that neutrophils can influence tumor development and invasive migration through various mechanisms, thereby exerting their anti-tumor effects. Conversely, they can also facilitate tumorigenesis and proliferation, as well as affect the normal physiological functions of other immune cells, thus exerting pro-tumor effects. Moreover, neutrophils are influenced by tumor cells and their unique microenvironment, which in turn affects their heterogeneity and plasticity. Neutrophils interact with tumor cells to regulate various aspects of their life activities precisely. This paper also identifies unresolved issues in the research concerning the bidirectional role of neutrophils in tumorigenesis and tumor development, offering new opportunities and challenges for advancing our understanding. This, in turn, can aid in the proper application of these insights to clinical treatment strategies.

Systemic therapy for unresectable hepatocellular carcinoma (HCC) has progressed with the development of multiple kinases, such as vascular endothelial growth factor (VEGF) signaling, targeting cancer growth and angiogenesis. Additionally, the efficacy of sorafenib, regorafenib, lenvatinib, ramucirumab, and cabozantinib has been demonstrated in various clinical trials, and they are now widely used in clinical practice. Furthermore, the development of effective immune checkpoint inhibitors has progressed in systemic therapy for unresectable HCC, and atezolizumab + bevacizumab (atezo/bev) therapy and durvalumab + tremelimumab therapy are now recommended as first-line treatment. Atezo/bev therapy, which combines an anti-programmed cell death 1 ligand 1 antibody with an anti-VEGF antibody, is the first cancer immunotherapy to demonstrate efficacy against unresectable HCC. With the increasing popularity of these treatments, VEGF inhibition is attracting attention from the perspective of its anti-angiogenic effects and impact on the cancer-immune cycle. In this review, we outline the role of VEGF in the tumor immune microenvironment and cancer immune cycle in HCC and outline the potential immune regulatory mechanisms of VEGF. Furthermore, we consider the potential significance of the dual inhibition of angiogenesis and immune-related molecules by VEGF, and ultimately aim to clarify the latest treatment strategies that maximizes efficacy.

Oncolytic viruses have emerged as a highly promising modality for cancer treatment due to their ability to replicate specifically within tumors, carry therapeutic genes, and modulate the immunosuppressive tumor microenvironment through various mechanisms. Additionally, they show potential synergy with immune checkpoint inhibitors. A study report indicates that from 2000 to 2020, 49.5% of oncolytic viruses were administered intratumorally and 35% intravenously during clinical trials. However, both administration methods face significant challenges, particularly with intravenous delivery, which encounters issues such as non-specific tissue uptake, neutralizing antibody responses, and antiviral effects mediated by various immune cells. Despite extensive research into the antiviral roles of CD8+ T cells and NK cells in oncolytic virus therapy, neutrophils-constituting approximately 50% to 70% of human peripheral blood leukocytes-have received relatively little attention. Neutrophils are the most abundant leukocyte subset in peripheral circulation, known for their phagocytic activity. Beyond their traditional roles in bacterial and fungal infections, emerging literature suggests that neutrophils also play a critical role in the body's antiviral responses. Given the gaps in understanding the role of neutrophils in oncolytic virus therapy, this article reviews current literature on this topic. It aims to provide a theoretical foundation for developing oncolytic virus-based cancer therapies and enhancing their anti-tumor efficacy in future clinical treatments.

Melanoma is a malignant, highly metastatic neoplasm showing increasing morbidity and mortality. Tumor invasion and angiogenesis are based on remodeling of the extracellular matrix (ECM). Selective inhibition of functional components of cell-ECM interaction, such as hyaluronic acid (HA), matrix metalloproteinases (MMPs), and integrins, may inhibit tumor progression and enhance the efficacy of combination treatment with immune checkpoint inhibitors (ICIs), chemotherapy, or immunotherapy. In this review, we combine the results of different approaches targeting extracellular matrix elements in melanoma in preclinical and clinical studies. The identified limitations of many approaches, including side effects, low selectivity, and toxicity, indicate the need for further studies to optimize therapy. Nevertheless, significant progress in expanding our understanding of tumor biology and the development of targeted therapies holds great promise for the early approaches developed several decades ago to inhibit metastasis through ECM targeting.

Lymphoma, a malignancy of the lymphatic system, which is critical for maintaining the body's immune defenses, has become a focal point in recent research due to its intricate interplay with neutrophils-white blood cells essential for combating infections and inflammation. Unlike prior perceptions associating neutrophils only with tumor support, contemporary studies underscore their intricate and multifaceted involvement in the immune response to lymphoma. Recognizing the nuanced participation of neutrophils in lymphoma is crucial for developing innovative treatments to improve patient outcomes.

The application of nanomaterials in tumor therapy is increasingly widespread, offering more possibilities for enhanced tumor therapy. However, the unclear biological distribution and metabolism of nanomaterials may lead to immune rejection or inflammatory reactions, posing numerous challenges to their clinical translation. The rich diversity and multifaceted functions of blood cells offer promising biological avenues for enhancing the application of nanoparticles in cancer therapy. Blood cell membranes, being made of naturally found components in the body, exhibit significant biocompatibility, which can reduce the body's immune rejection response, extend the drug's residence time in the bloodstream, and enhance its bioavailability. Integrating blood cell membranes with nanomaterials enhances tumor therapy by improving targeted delivery, prolonging circulation time, and evading immune responses. This review summarizes recent advancements in the application of blood cell membrane-coated nanomaterials for antitumor therapy, with a particular focus on their use in photodynamic and photothermal treatments. Additionally, it explores their potential for synergistic effects when combined with other therapeutic modalities.

This study investigates the significance of systemic pan-immune inflammation value (PIV) prior to concurrent chemoradiotherapy (CCRT) in predicting the therapeutic efficacy as well as prognosis of patients with locally advanced cervical squamous cell carcinoma.

A retrospective analysis was conducted on the clinical data of 847 patients with locally advanced cervical cancer (LACC) treated at the Second Hospital of Jilin University between 2016 and 2020. All patients underwent radical CCRT, including platinum-based sensitizing chemotherapy. The PIV was measured as given by: (platelet count × neutrophil count × monocyte count)/lymphocyte count. Logistic regression analysis was utilized to study the effect of PIV on therapeutic response in LACC patients and Kaplan-Meier survival together with Cox proportional hazard model to assess its impact on prognosis.

With the therapeutic effect as the endpoint, the optimal cutoff of PIV (356.0099) was signified via the receiver operating characteristics curve, and patients were grouped and compared based on this value. PIV was determined as an independent predictor of the therapeutic effect in CCRT for LACC (hazard ratio (HR) 1.696, 95% confidence interval (CI) 1.111-2.590). PIV was also an independent predictor of overall survival (OS) (HR 0.540, 95% CI 0.409-0.713, p<0.001) as well as disease-free survival (DFS) (HR 0.680, 95% CI 0.528-0.876, p=0.003). Compared to the low-PIV group, it was noted that individuals with a high PIV exhibited a poorer therapeutic effect and shorter OS and DFS.

Patients with LACC and high PIV had poorer therapeutic outcomes and shorter OS and DFS. Our results may provide PIV as a new prognostic biomarker for LACC, if future prospective studies with large patient numbers support our findings.

Gene regulatory networks (GRNs) reveal the intricate interactions between and among genes, and understanding these interactions is essential for revealing the molecular mechanisms of cancer. However, existing algorithms for constructing GRNs may confuse regulatory relationships and complicate the determination of network directionality.

We propose a new method to construct GRNs based on causal strength and ensemble regression (CSER) to overcome these issues. CSER uses conditional mutual inclusive information to quantify the causal associations between genes, eliminating indirect regulation and marginal genes. It considers linear and nonlinear features and uses ensemble regression to infer the direction and interaction (activation or regression) from regulatory to target genes.

Compared to traditional algorithms, CSER can construct directed networks and infer the type of regulation, thus demonstrating higher accuracy on simulated datasets. Here, using real gene expression data, we applied CSER to construct a colorectal cancer GRN and successfully identified several key regulatory genes closely related to colorectal cancer (CRC), including ADAMDEC1, CLDN8, and GNA11.

Importantly, by integrating immune cell and microbial data, we revealed the complex interactions between the CRC gene regulatory network and the tumor microenvironment, providing additional new biomarkers and therapeutic targets for the early diagnosis and prognosis of CRC.

Increasing evidence has revealed that granulocyte has a critical role in tumorigenesis and progression. In this study, Mendelian randomization (MR) analysis was utilized for estimating the causal association between neutrophil percentage and melanoma skin cancer, eosinophil percentage and melanoma skin cancer, basophil percentage and melanoma skin cancer, respectively.

The Genome-Wide Association Study (GWAS) ids for melanoma skin cancer, neutrophil percentage, eosinophil percentage and basophil percentage were derived from Integrative Epidemiology Unit (IEU) Open GWAS database. The univariable MR (UVMR) analysis was conducted to estimate the risk using MR-Egger, weighted median, inverse variance weighted (IVW). In addition, sensitivity analysis was conducted to assess the reliability of UVMR results. Finally, the multivariable MR (MVMR) analysis was performed to investigate causality between neutrophil percentage and eosinophil percentage in the presence of both and melanoma skin cancer.

The UVMR indicated that neutrophil percentage and eosinophil percentage were significantly and causally related to melanoma skin cancer, with neutrophil percentage [p = 0.025, odds ratio (OR) = 1.002] as a risk factor and eosinophil percentage (p = 7.04E-06, OR = 0.997) as a protective factor. Moreover, MVMR analysis indicated eosinophil percentage remained the protective factor (p = 0.003, OR = 0.998), while the causality of neutrophil percentage and melanoma skin cancer became insignificant (p > 0.05).

The causal relationships of neutrophil percentage and melanoma skin cancer, eosinophil percentage and melanoma skin cancer were shown by this study, which provided a reference for subsequent research and treatment related to melanoma skin cancer.

Colorectal cancer (CRC) is a significant health issue, with notable incidence rates in Norway. The immune response plays a dual role in CRC, offering both protective effects and promoting tumor growth. This research aims to provide a detailed screening of immune-related genes and identify specific genes in CRC and adenomatous polyps within the Norwegian population, potentially serving as detection biomarkers.

The study involved 69 patients (228 biopsies) undergoing colonoscopy, divided into CRC, adenomatous polyps, and control groups. We examined the expression of 579 immune genes through nCounter analysis emphasizing differential expression in tumor versus adjacent non-tumorous tissue and performed quantitative reverse transcription polymerase chain reaction (RT-qPCR) across patient categories.

Key findings include the elevated expression of CXCL1, CXCL2, IL1B, IL6, CXCL8 (IL8), PTGS2, and SPP1 in CRC tissues. Additionally, CXCL1, CXCL2, IL6, CXCL8, and PTGS2 showed significant expression changes in adenomatous polyps, suggesting their early involvement in carcinogenesis.

This study uncovers a distinctive immunological signature in colorectal neoplasia among Norwegians, highlighting CXCL1, CXCL2, IL1B, IL6, CXCL8, PTGS2, and SPP1 as potential CRC biomarkers. These findings warrant further research to confirm their role and explore their utility in non-invasive screening strategies.

Both nonalcoholic fatty liver disease (NAFLD) and colorectal cancer (CRC) are prevalent worldwide. The effects of concomitant NAFLD on the risk of colorectal liver metastasis (CRLM) and its mechanisms have not been definitively elucidated.

We observed the effect of concomitant NAFLD on CRLM in the mouse model and explored the underlying mechanisms of specific myeloid-derived suppressor cells (MDSCs) recruitment and then tested the therapeutic application based on the mechanisms. Finally we validated our findings in the clinical samples.

Here we prove that in different mouse models, NAFLD induces F4/80+ Kupffer cells to secret chemokine CXCL5 and then recruits CXCR2+ MDSCs to promote the growth of CRLM. CRLM with NAFLD background is refractory to the anti-PD-1 monoclonal antibody treatment, but when combined with Reparixin, an inhibitor of CXCR1/2, dual therapy cures the established CRLM in mice with NAFLD. Our clinical studies also indicate that fatty liver diseases increase the infiltration of CXCR2+ MDSCs, as well as the hazard of liver metastases in CRC patients.

Collectively, our findings highlight the significance of selective CXCR2+/CD11b+/Gr-1+ subset myeloid cells in favoring the development of CRLM with NAFLD background and identify a pharmaceutical medicine that is already available for the clinical trials and potential treatment.

The involvement of the prostaglandin E2 (PGE2) system in cancer progression has long been recognized. PGE2 functions as an autocrine and paracrine signaling molecule with pleiotropic effects in the human body. High levels of intratumoral PGE2 and overexpression of the key metabolic enzymes of PGE2 have been observed and suggested to contribute to tumor progression. This has been claimed for different types of solid tumors, including, but not limited to, lung, breast, and colon cancer. PGE2 has direct effects on tumor cells and angiogenesis that are known to promote tumor development. However, one of the main mechanisms behind PGE2 driving cancerogenesis is currently thought to be anchored in suppressed antitumor immunity, thus providing possible therapeutic targets to be used in cancer immunotherapies. EP2 and EP4, two receptors for PGE2, are emerging as being the most relevant for this purpose. This review aims to summarize the known roles of PGE2 in the immune system and its functions within the tumor microenvironment. SIGNIFICANCE STATEMENT: Prostaglandin E2 (PGE2) has long been known to be a signaling molecule in cancer. Its presence in tumors has been repeatedly associated with disease progression. Elucidation of its effects on immunological components of the tumor microenvironment has highlighted the potential of PGE2 receptor antagonists in cancer treatment, particularly in combination with immune checkpoint inhibitor therapeutics. Adjuvant treatment could increase the response rates and the efficacy of immune-based therapies.

The prognostic value of the neutrophil-lymphocyte ratio, platelet-lymphocyte ratio and monocyte-lymphocyte ratio in patients with melanoma has yielded controversial results in the literature. A retrospective single-centre cohort study was conducted from 1998 to 2020, including patients diagnosed with invasive melanoma. A total of 2,721 patients were included in the study. The median follow-up was 8.23 years (IQR 4.41-13.25). The median baseline neutrophil- lymphocyte ratio, platelet-lymphocyte ratio and monocyte-lymphocyte ratio values increased significantly (p < 0.001) with the increasing American Joint Committee on Cancer stage. The optimal cut-off values for neutrophil-lymphocyte ratio, platelet-lymphocyte ratio and monocyte-lymphocyte ratio were determined as 2.1, 184 and 0.2, respectively. In the multivariate analysis, high levels of neutrophil-lymphocyte ratio (≥ 2.1), platelet-lymphocyte ratio (≥ 184) and monocyte-lymphocyte ratio (≥ 0.2) were independently associated with significantly shorter melanoma-specific survival (neutrophil-lymphocyte ratio: HR 1.30, 95% CI 1.06-1.60, p = 0.013; platelet-lymphocyte ratio: HR 1.37, 95% CI 1.06-1.76, p = 0.014; monocyte- lymphocyte ratio: HR 1.29, 95% CI 1.05-1.58, p = 0.015) and overall survival (neutrophil-lymphocyte ratio: HR 1.39, 95% CI 1.19-1.64, p < 0.001; platelet- lymphocyte ratio: HR 1.44, 95% CI 1.19-1.74, p < 0.001; monocyte-lymphocyte ratio: HR 1.42, 95% CI 1.21-1.66, p < 0.001). High levels of neutrophil- lymphocyte ratio and monocyte-lymphocyte ratio were also associated with poor relapse-free survival, while platelet-lymphocyte ratio was not. In conclusion, baseline neutrophil-lymphocyte ratio, platelet-lymphocyte ratio and monocyte-lymphocyte ratio were identified as independent predictors for the prognosis of melanoma.

The aim was to explore the value of neutrophil-lymphocyte ratio (NLR) as a biomarker for predicting the prognosis or diagnosis in adrenocortical carcinoma (ACC).

We identified 262 patients with adrenal gland disease who underwent operation at our institution between 2013 and 2018. According to postoperative pathology, patients were divided into 2 groups: ACC and non-ACC groups. The neutrophil and lymphocyte count of patients were recorded. Within the intergroup comparison, data obtained from ACC and non-ACC groups were evaluated using ANOVA test. The cut-off values of NLR for the prognosis in ACC were determined according to 3 methods.

The NLR values of ACC and non-ACC groups were 5.36 ± 5.30 and (1.73 ± 0.26) ∼ (2.56 ± 1.35), respectively (P < .001). NLR carry a differential property was evaluated with ROC curve to distinguish the above 2 groups. The cut-off value of NLR was estimated as 2.65 according to the Youden index. With this value, sensitivity was found as 67.5%, specificity was 83.8% and AUC was 0.749 (P < .001, confidence interval = 0.638-0.860). In ACC, the higher NLR group was not shown significantly poorer overall survival than the lower NLR group (NLR ≥2.65 vs. NLR < 2.65, NLR ≥5 vs. NLR <5, NLR ≥5.36 vs. NLR <5.36) (P > .05).

According to the data in this study, it can be said that adrenocortical tumors are likely to be malignant by 67.5% if the NLR value is greater than 2.65. When we use the NLR to predict the prognosis of ACC, there is not statistically significant.

T-cell acute lymphoblastic leukemia (T-ALL)/T-cell lymphoblastic lymphoma (T-LBL) is an uncommon but highly aggressive hematological malignancy. It has high recurrence and mortality rates and is challenging to treat. This study conducted bioinformatics analyses, compared genetic expression profiles of healthy controls with patients having T-ALL/T-LBL, and verified the results through serological indicators. Data were acquired from the GSE48558 dataset from Gene Expression Omnibus (GEO). T-ALL patients and normal T cells-related differentially expressed genes (DEGs) were investigated using the online analysis tool GEO2R in GEO, identifying 78 upregulated and 130 downregulated genes. Gene Ontology (GO) and protein-protein interaction (PPI) network analyses of the top 10 DEGs showed enrichment in pathways linked to abnormal mitotic cell cycles, chromosomal instability, dysfunction of inflammatory mediators, and functional defects in T-cells, natural killer (NK) cells, and immune checkpoints. The DEGs were then validated by examining blood indices in samples obtained from patients, comparing the T-ALL/T-LBL group with the control group. Significant differences were observed in the levels of various blood components between T-ALL and T-LBL patients. These components include neutrophils, lymphocyte percentage, hemoglobin (HGB), total protein, globulin, erythropoietin (EPO) levels, thrombin time (TT), D-dimer (DD), and C-reactive protein (CRP). Additionally, there were significant differences in peripheral blood leukocyte count, absolute lymphocyte count, creatinine, cholesterol, low-density lipoprotein, folate, and thrombin times. The genes and pathways associated with T-LBL/T-ALL were identified, and peripheral blood HGB, EPO, TT, DD, and CRP were key molecular markers. This will assist the diagnosis of T-ALL/T-LBL, with applications for differential diagnosis, treatment, and prognosis.

Colony-stimulating factors (CSFs) are key cytokines responsible for the production, maturation, and mobilization of the granulocytic and macrophage lineages from the bone marrow, which have been gaining attention for playing pro- and/or anti-tumorigenic roles in cancer. Head and neck cancers (HNCs) represent a group of heterogeneous neoplasms with high morbidity and mortality worldwide. Treatment for HNCs is still limited even with the advancements in cancer immunotherapy. Novel treatments for patients with recurrent and metastatic HNCs are urgently needed. This article provides an in-depth review of the role of hematopoietic cytokines such as granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor (M-CSF), and interleukin-3 (IL-3; also known as multi-CSF) in the HNCs tumor microenvironment. We have reviewed current results from clinical trials using CSFs as adjuvant therapy to treat HNCs patients, and also clinical findings reported to date on the therapeutic application of CSFs toxicities arising from chemoradiotherapy.

The pan-immune-inflammation value (PIV), which reflects the balance between the host immune and inflammatory status, is a readily available index for evaluating cancer outcomes. Until now, however, no study has demonstrated the clinical response of PIV to neoadjuvant immunochemotherapy (NICT) in esophageal squamous cell carcinoma (ESCC).

This retrospective study included 218 patients with ESCC who underwent NICT. The relationship between PIV and therapeutic response (pathological complete response [PCR]) and clinical outcomes (overall survival [OS] and disease-free survival [DFS]) was examined. Cox proportional, hazard-regression analyses and the Kaplan-Meier method were used for survival analyses. Recursive partitioning analysis (RPA) was used to establish a novel risk stratification model.

Sixty-six patients (30.3%) achieved PCR after NICT. Using PCR as the endpoint of interest, patients were compared in groups based on the optimal threshold. PIV was closely related to PCR (odds ratio [OR] 0.311, 95% confidence interval [CI] 0.140-0.690, P = 0.004). Compared with patients in the low PIV cohort, patients with high PIV had worse 3-year OS (58.7% vs. 83.6%, P < 0.001) and DFS (51.9% vs. 79.1%, P < 0.001). PIV was an independent predictor of OS (hazard ratio [HR] 2.364, 95% CI 1.183-4.724, P = 0.015) and DFS (HR 1.729, 95% CI 1.026-2.913, P = 0.040). Three risk groups with varied DFS and OS were staged by using an RPA method, and the prognostication accuracy was considerably improved.

Pretreatment PIV can predict the therapeutic efficacy of NICT for ESCC. Because of better prognostic stratification, pretreatment PIV is a novel, sensitive, and effective indicator in ESCC receiving NICT. The prognostic results of PIV need to be verified in additional prospective studies.

Immunotherapies have revolutionized the treatment paradigms of various types of cancers. However, most of these immunomodulatory strategies focus on harnessing adaptive immunity, mainly by inhibiting immunosuppressive signaling with immune checkpoint blockade, or enhancing immunostimulatory signaling with bispecific T cell engager and chimeric antigen receptor (CAR)-T cell. Although these agents have already achieved great success, only a tiny percentage of patients could benefit from immunotherapies. Actually, immunotherapy efficacy is determined by multiple components in the tumor microenvironment beyond adaptive immunity. Cells from the innate arm of the immune system, such as macrophages, dendritic cells, myeloid-derived suppressor cells, neutrophils, natural killer cells, and unconventional T cells, also participate in cancer immune evasion and surveillance. Considering that the innate arm is the cornerstone of the antitumor immune response, utilizing innate immunity provides potential therapeutic options for cancer control. Up to now, strategies exploiting innate immunity, such as agonists of stimulator of interferon genes, CAR-macrophage or -natural killer cell therapies, metabolic regulators, and novel immune checkpoint blockade, have exhibited potent antitumor activities in preclinical and clinical studies. Here, we summarize the latest insights into the potential roles of innate cells in antitumor immunity and discuss the advances in innate arm-targeted therapeutic strategies.

Purpose: To assess the impact of neoadjuvant chemotherapy (NACT) on the tumor immune microenvironment (TIME) in gynaecological tumors, with a focus on understanding the potential for enhanced combination therapies.Methods: We systematically queried the PubMed, Embase, and Cochrane databases, encompassing reviews, clinical trials, and case studies, to undertake a thorough analysis of the impact of NACT on the TIME of gynaecological tumors.Results: NACT induces diverse immune microenvironment changes in gynaecological tumors. In cervical cancer, NACT boosts immune-promoting cells, enhancing tumor clearance. Ovarian cancer studies yield variable outcomes, influenced by patient-specific factors and treatment regimens. Limited research exists on NACT's impact on endometrial cancer's immune microenvironment, warranting further exploration. In summary, NACT-induced immune microenvironment changes display variability. Clinical trials highlight personalized immunotherapy's positive impact on gynaecological tumor prognosis, suggesting potential avenues for future cancer treatments. However, rigorous investigation is needed to determine the exact efficacy and safety of combining NACT with immunotherapy.Conclusion: This review provides a solid foundation for the development of late-stage immunotherapy and highlights the importance of therapeutic strategies targeting immune cells in TIME in anti-tumor therapy.

Several researches have shown that pan-immune-inflammation value (PIV) is related to cancer prognosis in recent years. In esophageal squamous cell carcinoma (ESCC), nevertheless, the prognostic impact of PIV remains unclear. The present study sought to investigate the prognostic impact of preoperative PIV in ESCC with radical resection.

The data of 294 ESCC patients who received radical resection were retrospectively analyzed. Based on analyzing the non-linear relationship between PIV and cancer-specific survival (CSS), the optimal cutoff value for PIV was calculated by the restricted cubic spline (RCS) model. Cox proportional hazards regression was carried out to identify the prognostic factors. A risk stratification model was established by recursive partitioning analysis (RPA). The performance of the RPA-based model was assessed by the decision curve analysis (DCA) and receiver operating characteristic (ROC).

The RCS visualized the non-linear relationship between PIV and CSS (P < 0.0001). Then patients were then divided into high and low groups based on the optimal threshold of 308.2. The 5-year CSS (17.7 % vs. 48.3 %, P < 0.001) was significantly worse in patients with high PIV than those in the low group. Subgroup analyses confirmed that patients with low PIV also achieved better 5-year survival at different pathological tumor node metastasis (pTNM) stages (pTNM I: P = 0.022; pTNM II: P = 0.001; pTNM III: P = 0.011). PIV served as an independent prognostic factor of CSS (hazard ratio = 1.983, P < 0.001). A new staging involving three risk groups with significantly different CSS was developed using RPA algorithms based on pTNM and PIV. Compared with the pTNM classification, the RPA-based model exhibited significantly superior performance for prognostication.

The present study confirmed the prognostic impact of PIV in ESCC who treated with radical resection. PIV was associated with the tumor stage and prognosis, which might be useful in the preoperative assessment of ESCC.

MUC16 (CA125) is a commonly used tumor marker for ovarian cancer screening and reported to be an immunosuppressive factor by acting on the sialic acid-binding immunoglobulin-like lectin-9 (Siglec-9) on the surface of natural killer cells (NK cells), B cells, and monocytes. However, the role of MUC16 on neutrophils in the tumor microenvironment remains to be further explored.

The correlation between the proportion and count of peripheral blood cells, serum inflammatory-related factors and serum MUC16 (CA125) level in patients was constructed based on clinical samples. RNAseq data was obtained from TCGA and sequencing of ovarian cancer tissues, followed by TIMER immune cell infiltration and correlation analysis. Ovarian cancer organoid was constructed to stimulate neutrophils with immunophenotype identification by qPCR and flow cytometry. MUC16 protein stimulation to neutrophils validated the role of MUC16 under the analysis of RNA sequencing and inhibition of NK cytotoxicity in vitro.

The serum MUC16 level was positively correlated with the proportion and count of peripheral blood neutrophils, neutrophil-to-lymphocyte ratio (NLR) and inflammatory factors IL-6, IL-8, IL-10 and IL-2R. Siglec-9, the receptor of MUC16, was expressed on neutrophils and was positively correlated to neutrophil infiltration in ovarian cancer. After the stimulation of ovarian cancer organoids and MUC16 respectively, the proportions of CD11b+, CD66b+, and ICAM-1+ neutrophils were significantly increased, while the proportion of CXCR4+ neutrophils was slightly decreased, with increasing of of inflammatory factors MMP9, IL-8, OSM, IL-1β, TNF-α, CXCL3, and ROS. RNA-sequencing analysis revealed that inflammatory response, TNFA signaling pathway, and IL6-related pathway were upregulated in MUC16-stimulated neutrophils, accompanied by high expression of immunosuppression-related factors HHLA2, IL-6, TNFRSF9, ADORA2A, CD274 (PD-L1), and IDO1. NK cytotoxicity was decreased when treated by supernanant of MUC16-stimulated neutrophils in vitro.

MUC16 acted on neutrophils by Siglec-9 leading to an inflammatory and immunosuppressive phenotype in ovarian cancer.

Hepatocellular carcinoma (HCC) is one of the most prevalent tumors worldwide and the leading contributor to cancer-related deaths. The progression and metastasis of HCC are closely associated with altered mitochondrial metabolism, including mitochondrial stress response. Mitokines, soluble proteins produced and secreted in response to mitochondrial stress, play an essential immunomodulatory role. Immunotherapy has emerged as a crucial treatment option for HCC. However, a positive response to therapy is typically dependent on the interaction of tumor cells with immune regulation within the tumor microenvironment. Therefore, exploring the specific immunomodulatory mechanisms of mitokines in HCC is essential for improving the efficacy of immunotherapy. This study provides a comprehensive overview of the association between HCC and the immune microenvironment and highlights recent progress in understanding the involvement of mitochondrial function in preserving liver function. In addition, a systematic review of mitokines-mediated immunomodulation in HCC is presented. Finally, the potential diagnostic and therapeutic roles of mitokines in HCC are prospected and summarized. Recent progress in mitokine research represents a new prospect for mitochondrial therapy. Considering the potential of mitokines to regulate immune function, investigating them as a relevant molecular target holds great promise for the diagnosis and treatment of HCC.

Breast cancer (BC) is a highly heterogeneous disease, and although immunotherapy has recently increased patient survival in a number of solid and hematologic malignancies, most BC subtypes respond poorly to immune checkpoint blockade therapy (ICB). B cells, particularly those that congregate in tertiary lymphoid structures (TLS), play a significant role in antitumour immunity. However, B-cell heterogeneity at single-cell resolution and its clinical significance with TLS in BC need to be explored further.

Primary tumour lesions and surrounding normal tissues were taken from 14 BC patients, totaling 124,587 cells, for single-cell transcriptome sequencing and bioinformatics analysis.

Based on the usual markers, the single-cell transcriptome profiles were classified into various clusters. A thorough single-cell study was conducted with a focus on tumour-infiltrating B cells (TIL-B) and tumour-associated neutrophils (TAN). TIL-B was divided into five clusters, and unusual cell types, such as follicular B cells, which are strongly related to immunotherapy efficacy, were identified. In BC, TAN and TIL-B infiltration are positively correlated, and at the same time, compared with TLS-high, TAN and TIL-B in TLS-low group are significantly positively correlated.

In conclusion, our study highlights the heterogeneity of B cells in BC, explains how B cells and TLS contribute significantly to antitumour immunity at both the single-cell and clinical level, and offers a straightforward marker for TLS called CD23. These results will offer more pertinent information on the applicability and effectiveness of tumour immunotherapy for BC.

Neutrophils are the most abundant myeloid cells in the blood and are a considerable immunological component of the tumor microenvironment. However, their functional importance has often been ignored, as they have always been considered a mono-dimensional population of terminally differentiated, short-living cells. During the last decade, the use of cutting-edge, single-cell technologies has revolutionized the classical view of these cells, unmasking their phenotypic and functional heterogeneity. In this review, we summarize the emerging concepts in the field of neutrophils in cancer, by reviewing the recent literature on the heterogeneity of both circulating neutrophils and tumor-associated neutrophils, as well as their possible significance in tumor prognosis and resistance to immune checkpoint inhibitors.

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. The absence of effective early diagnostic methods and the limitations of conventional therapies have led to a growing interest in immunotherapy as a novel treatment approach for HCC. The liver serves as an immune organ and a recipient of antigens from the digestive tract, creating a distinctive immune microenvironment. Key immune cells, including Kupffer cells and cytotoxic T lymphocytes, play a crucial role in HCC development, thus offering ample research opportunities for HCC immunotherapy. The emergence of advanced technologies such as clustered regularly interspaced short palindromic repeats (CRISPR) and single-cell ribonucleic acid sequencing has introduced new biomarkers and therapeutic targets, facilitating early diagnosis and treatment of HCC. These advancements have not only propelled the progress of HCC immunotherapy based on existing studies but have also generated new ideas for clinical research on HCC therapy. Furthermore, this review analysed and summarised the combination of current therapies for HCC and the improvement of CRISPR technology for chimeric antigen receptor T cell therapy, instilling renewed hope for HCC treatment. This review comprehensively explores the advancements in immunotherapy for HCC, focusing on the use of new techniques.

Tissue engineering and regenerative medicine are pursuing clinical valid solutions to repair and restore function of damaged tissues or organs. This can be achieved in different ways, either by promoting endogenous tissue repair or by using biomaterials or medical devices to replace damaged tissues. The understanding of the interactions of the immune system with biomaterials and how immune cells participate in the process of wound healing are critical for the development of successful solutions. Until recently, it was thought that neutrophils participate only in the initial steps of an acute inflammatory response with the role of eliminating pathogenic agents. However, the appreciation that upon activation the longevity of neutrophils is highly increased and the fact that neutrophils are highly plastic cells and can polarize into different phenotypes led to the discovery of new and important actions of neutrophils. In this review, we focus on the roles of neutrophils in the resolution of the inflammatory response, in biomaterial-tissue integration and in the subsequent tissue repair/regeneration. We also discuss the potential of neutrophils for biomaterial-based immunomodulation.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and shows high global incidence and mortality rates. The liver is an immune-tolerated organ with a specific immune microenvironment that causes traditional therapeutic approaches to HCC, such as chemotherapy, radiotherapy, and molecular targeted therapy, to have limited efficacy. The dramatic advances in immuno-oncology in the past few decades have modified the paradigm of cancer therapy, ushering in the era of immunotherapy. Currently, despite the rapid integration of cancer immunotherapy into clinical practice, some patients still show no response to treatment. Therefore, a rational approach is to target the tumor microenvironment when developing the next generation of immunotherapy. This review aims to provide insights into the hepatic immune microenvironment in HCC and summarize the mechanisms of action and clinical usage of immunotherapeutic options for HCC, including immune checkpoint blockade, adoptive therapy, cytokine therapy, vaccine therapy, and oncolytic virus-based therapy.

Lymphangioleiomyomatosis (LAM) is a rare cystic lung disease caused by smooth muscle cell-like tumors containing tuberous sclerosis (TSC) gene mutations and found almost exclusively in females. Patient studies suggest LAM progression is estrogen dependent, an observation supported by in vivo mouse models. However, in vitro data using TSC-null cell lines demonstrate modest estradiol (E2) responses, suggesting E2 effects in vivo may involve pathways independent of direct tumor stimulation. We previously reported tumor-dependent neutrophil expansion and promotion of TSC2-null tumor growth in an E2-sensitive LAM mouse model. We therefore hypothesized that E2 stimulates tumor growth in part by promoting neutrophil production. Here we report that E2-enhanced lung colonization of TSC2-null cells is indeed dependent on neutrophils. We demonstrate that E2 induces granulopoiesis via estrogen receptor α in male and female bone marrow cultures. With our novel TSC2-null mouse myometrial cell line, we show that factors released from these cells drive E2-sensitive neutrophil production. Last, we analyzed single-cell RNA sequencing data from LAM patients and demonstrate the presence of tumor-activated neutrophils. Our data suggest a powerful positive feedback loop whereby E2 and tumor factors induce neutrophil expansion, which in turn intensifies tumor growth and production of neutrophil-stimulating factors, resulting in continued TSC2-null tumor growth.

Head and neck squamous cell carcinoma (HNSCC) is one of the most aggressive and heterogeneous groups of human neoplasms. HNSCC is characterized by high morbidity, accounting for 3% of all cancers, and high mortality with ~1.5% of all cancer deaths. It was the most common cancer worldwide in 2020, according to the latest GLOBOCAN data, representing the seventh most prevalent human malignancy. Despite great advances in surgical techniques and the application of modern combinations and cytotoxic therapies, HNSCC remains a leading cause of death worldwide with a low overall survival rate not exceeding 40-60% of the patient population. The most common causes of death in patients are its frequent nodal metastases and local neoplastic recurrences, as well as the relatively low response to treatment and severe drug resistance. Much evidence suggests that the tumour microenvironment (TME), tumour infiltrating lymphocytes (TILs) and circulating various subpopulations of immunocompetent cells, such regulatory T cells (CD4+CD25+Foxp3+Tregs), cytotoxic CD3+CD8+ T cells (CTLs) and CD3+CD4+ T helper type 1/2/9/17 (Th1/Th2/Th9/Th17) lymphocytes, T follicular helper cells (Tfh) and CD56dim/CD16bright activated natural killer cells (NK), carcinoma-associated fibroblasts (CAFs), myeloid-derived suppressor cells (MDSCs), tumour-associated neutrophils (N1/N2 TANs), as well as tumour-associated macrophages (M1/M2 phenotype TAMs) can affect initiation, progression and spread of HNSCC and determine the response to immunotherapy. Rapid advances in the field of immuno-oncology and the constantly growing knowledge of the immunosuppressive mechanisms and effects of tumour cancer have allowed for the use of effective and personalized immunotherapy as a first-line therapeutic procedure or an essential component of a combination therapy for primary, relapsed and metastatic HNSCC. This review presents the latest reports and molecular studies regarding the anti-tumour role of selected subpopulations of immunocompetent cells in the pathogenesis of HNSCC, including HPV+ve (HPV+) and HPV-ve (HPV-) tumours. The article focuses on the crucial regulatory mechanisms of pro- and anti-tumour activity, key genetic or epigenetic changes that favour tumour immune escape, and the strategies that the tumour employs to avoid recognition by immunocompetent cells, as well as resistance mechanisms to T and NK cell-based immunotherapy in HNSCC. The present review also provides an overview of the pre- and clinical early trials (I/II phase) and phase-III clinical trials published in this arena, which highlight the unprecedented effectiveness and limitations of immunotherapy in HNSCC, and the emerging issues facing the field of HNSCC immuno-oncology.

Annexin A1 (AnxA1) is highly secreted by neutrophils and binds to formyl peptide receptors (FPRs) to trigger anti-inflammatory effects and efferocytosis. AnxA1 is also expressed in the tumor microenvironment, being mainly attributed to cancer cells. As recruited neutrophils are player cells at the tumor sites, the role of neutrophil-derived AnxA1 in lung melanoma metastasis was investigated here. Melanoma cells and neutrophils expressing AnxA1 were detected in biopsies from primary melanoma patients, which also presented higher levels of serum AnxA1 and augmented neutrophil-lymphocyte ratio (NLR) in the blood. Lung melanoma metastatic mice (C57BL/6; i.v. injected B16F10 cells) showed neutrophilia, elevated AnxA1 serum levels, and higher labeling for AnxA1 in neutrophils than in tumor cells at the lungs with metastasis. Peritoneal neutrophils collected from naïve mice were co-cultured with B16F10 cells or employed to obtain neutrophil-conditioned medium (NCM; 18 h incubation). B16F10 cells co-cultured with neutrophils or with NCM presented higher invasion, which was abolished if B16F10 cells were previously incubated with FPR antagonists or co-cultured with AnxA1 knockout (AnxA1^-/-) neutrophils. The depletion of peripheral neutrophils during lung melanoma metastasis development (anti-Gr1; i.p. every 48 h for 21 days) reduced the number of metastases and AnxA1 serum levels in mice. Our findings show that AnxA1 secreted by neutrophils favors melanoma metastasis evolution via FPR pathways, addressing AnxA1 as a potential biomarker for the detection or progression of melanoma.

KIF11 is one of the 45 family members of kinesin superfamily proteins that functions as a motor protein in mitosis. Emerging evidence revealed that KIF11 plays pivotal roles in cancer initiation, development, and progression. However, the prognostic, oncological, and immunological values of KIF11 have not been comprehensively explored in pan-cancer. In present study, we comprehensively interrogated the role of KIF11 in tumor progression, tumor stemness, genomic heterogeneity, tumor immune infiltration, immune evasion, therapy response, and prognosis of cohorts from various cancer types. In general, KIF11 was significantly upregulated in tumors compared with paired normal tissues. KIF11 showed strong relationships with pathological stage, prognosis, tumor stemness, genomic heterogeneity, neoantigens, ESTIMATE, immune checkpoint, and drug sensitivity. The methylation level of KIF11 decreased in most cancers and was correlated with the survival probability in different human cancers. The expression of KIF11 was diverse in different molecular and immune subtypes and remarkably correlated with immune cell infiltration in the tumor microenvironment. Comparative study revealed that KIF11 was a powerful biomarker and associated with immune, targeted, and chemotherapeutic outcomes in various cancers. In addition, KIF11 interaction and coexpression networks mainly participated in the regulation of cell cycle, cell division, p53 signaling pathway, DNA repair and recombination, chromatin organization, antigen processing and presentation, and drug resistance. Our pan-cancer analysis provides a comprehensive understanding of the functions of KIF11 in oncogenesis, progression, and therapy in different cancers. KIF11 may serve as a potential prognostic and immunological pan-cancer biomarker. Moreover, KIF11 could be a novel target for tumor immunotherapy.

Chimeric antigen receptor (CAR)-T adoptive cell therapy is one of the most promising advanced therapies for the treatment of cancer, with unprecedented outcomes in haematological malignancies. However, it still lacks efficacy in solid tumours, possibly because engineered T cells become inactive within the immunosuppressive tumour microenvironment (TME). In the TME, cells of the myeloid lineage (M) are among the immunosuppressive cell types with the highest tumour infiltration rate. These cells interact with other immune cells, mediating immunosuppression and promoting angiogenesis. Recently, the development of CAR-M cell therapies has been put forward as a new candidate immunotherapy with good efficacy potential. This alternative CAR strategy may increase the efficacy, survival, persistence, and safety of CAR treatments in solid tumours. This remains a critical frontier in cancer research and opens up a new possibility for next-generation personalised medicine to overcome TME resistance. However, the exact mechanisms of action of CAR-M and their effect on the TME remain poorly understood. Here, we summarise the basic, translational, and clinical results of CAR-innate immune cells and CAR-M cell immunotherapies, from their engineering and mechanistic studies to preclinical and clinical development.

Malignancy is one of the common diseases with high mortality worldwide and the most important obstacle to improving the overall life expectancy of the population in the 21st century. Currently, single or combined treatments, including surgery, chemotherapy, and radiotherapy, are still the mainstream regimens for tumor treatment, but they all present significant side effects on normal tissues and organs, such as organ hypofunction, energy metabolism disorders, and various concurrent diseases. Based on this, theranostic measures for the highly selective killing of tumor cells have always been a hot area in cancer-related fields, among which photodynamic therapy (PDT) is expected to be an ideal candidate for practical clinical application due to its precise targeting and excellent safety performance, so-called PDT refers to a therapeutic method mainly composed of photosensitizers (PSs), laser light, and reactive oxygen species (ROS). Photoimmunotherapy (PIT), a combination of PDT and immunotherapy, can induce systemic antitumor immune responses and inhibit continuing growth and distant metastasis of residual tumor cells, demonstrating a promising application prospect. This article reviews the types of immune responses that occur in the host after PDT treatment, including innate and adaptive immunity. To further help PIT-related drugs improve their pharmacokinetic properties and bioavailability, we highlight the potential improvement of photodynamic immunotherapy from three aspects: immunostimulatory agents, tumor-associated antigens (TAAs) as well as different immune cells. Finally, we focus on recent advances in various strategies and shed light on their corresponding mechanisms of immune activation and possible clinical applications such as cancer vaccines. Having discovered the inherent potential of PDT and the mechanisms that PDT triggers host immune responses, a variety of immunotherapeutic strategies have been investigated in parallel with approaches to improve PDT efficiency. However, it remains to be further elucidated under what conditions the immune effect induced by PDT can achieve tumor immunosuppression and to what extent PDT-induced antitumor immunity will lead to complete tumor rejection. Currently, PIT presents several outstanding intractable challenges, such as the aggregation ability of PSs locally in tumors, deep tissue penetration ability of laser light, immune escape, and biological toxicity, and it is hoped that these issues raised will help to point out the direction of preclinical research on PIT and accelerate its transition to clinical practice.

Background: Breast cancer is the most common form of cancer in women worldwide. Advances in the early diagnosis and treatment of cancer in the last decade have progressively decreased the cancer mortality rate, and in recent years, immunotherapy has emerged as a relevant tool against cancer. HER2+ and triple-negative breast cancers (TNBCs) are considered more immunogenic and suitable for this kind of treatment due to the higher rate of tumor-infiltrating lymphocytes (TILs) and programmed death ligand 1 (PD-L1) expression. In TNBC, genetic aberrations further favor immunogenicity due to more neo-antigens in cancer cells. Methods: This review summarizes the principal ongoing conventional and investigational immunotherapies in breast cancer. Particularly, immune checkpoint inhibitors (ICIs) and their use alone or combined with DNA damage repair inhibitors (DDRis) are described. Then, the issue on immunotherapy with monoclonal antibodies against HER-2 family receptors is updated. Other investigational immunotherapies include a new schedule based on the interferon beta-interleukin-2 sequence that was given in ER+ metastatic breast cancer patients concomitant with anti-estrogen therapy, which surprisingly showed promising results. Results: Based on the scientific literature and our own findings, the current evaluation of tumor immunogenicity and the conventional model of adjuvant chemotherapy (CT) are questioned. Conclusions: A novel strategy based on additional prolonged adjuvant immunotherapy combined with hormone therapy or alternated with CT is proposed.

Cancer stem cells (CSC) are the minor population of cancer originating cells that have the capacity of self-renewal, differentiation, and tumorigenicity (when transplanted into an immunocompromised animal). These low-copy number cell populations are believed to be resistant to conventional chemo and radiotherapy. It was reported that metabolic adaptation of these elusive cell populations is to a large extent responsible for their survival and distant metastasis. Warburg effect is a hallmark of most cancer in which the cancer cells prefer to metabolize glucose anaerobically, even under normoxic conditions. Warburg's aerobic glycolysis produces ATP efficiently promoting cell proliferation by reprogramming metabolism to increase glucose uptake and stimulating lactate production. This metabolic adaptation also seems to contribute to chemoresistance and immune evasion, a prerequisite for cancer cell survival and proliferation. Though we know a lot about metabolic fine-tuning in cancer, what is still in shadow is the identity of upstream regulators that orchestrates this process. Epigenetic modification of key metabolic enzymes seems to play a decisive role in this. By altering the metabolic flux, cancer cells polarize the biochemical reactions to selectively generate "onco-metabolites" that provide an added advantage for cell proliferation and survival. In this review, we explored the metabolic-epigenetic circuity in relation to cancer growth and proliferation and establish the fact how cancer cells may be addicted to specific metabolic pathways to meet their needs. Interestingly, even the immune system is re-calibrated to adapt to this altered scenario. Knowing the details is crucial for selective targeting of cancer stem cells by choking the rate-limiting stems and crucial branch points, preventing the formation of onco-metabolites.