In recent years, immunotherapy has gradually become one of the main strategies for cancer treatment, with immune checkpoint inhibitors (ICIs) offering new possibilities for tumor therapy. However, some cancer patients exhibit low responses and resistance to ICIs treatment. T cell exhaustion, a process associated with tumor progression, refers to a subset of T cells that progressively lose effector functions and exhibit increased expression of inhibitory receptors. These exhausted T cells are considered key players in the therapeutic efficacy of immune checkpoint inhibitors. Therefore, understanding the impact of T cell exhaustion on tumor immunotherapy and the underlying mechanisms is critical for improving clinical treatment outcomes. Several elegant studies have provided insights into the prognostic value of exhausted T cells in cancers. In this review, we highlight the process of exhausted T cells and its predictive value in various cancers, as well as the relevant mechanisms behind it, providing new insights into the immunotherapy of cancer.

Neutrophils are among the most abundant immune cell types in the tumour microenvironment and have been associated with poor outcomes across multiple cancer types. Yet despite mounting evidence of their role in tumour progression, therapeutic strategies targeting neutrophils have only recently gained attention and remain limited in scope. This is probably due to the increasing number of distinct neutrophil subtypes identified in cancer and the limited understanding of the mechanisms by which these subsets influence tumour progression and immune evasion. In this Review, we discuss the spectrum of neutrophil subtypes - including those with antitumour activity - and their potential to polarize towards tumour-suppressive phenotypes. We explore the molecular pathways and effector functions by which neutrophils modulate cancer progression, with an emphasis on identifying tractable therapeutic targets. Finally, we examine emerging clinical trials aimed at modulating neutrophil lineages and consider their implications for patient outcomes.

Neutrophils have recently received increased attention in cancer because they contribute to all stages of cancer. Neutrophils are so far considered to have a short half-life. However, a growing body of literature has shown that tumor-associated neutrophils (TANs) acquire a prolonged lifespan. This review discusses recent work surrounding the mechanisms by which neutrophils can persist in the tumor microenvironment (TME). It also highlights different scenarios for therapeutic targeting of protumorigenic neutrophils, supporting the idea that, in tumors, inhibition of neutrophil recruitment is not sufficient because these cells can persist and remain hidden from current interventions. Hence, the elimination of long-lived neutrophils should be pursued to increase the efficacy of standard therapy.

Neutrophils are important components of the immune system and play a key role in defending against pathogenic infections and responding to inflammatory cues, including cancer. Their dysregulation indicates potential disease risk factors. However, their functional importance in disease progression has often been underestimated due to their short half-life, especially as there is limited information on the role of intratumoral neutrophils. Recent studies on their prominent role in cancer have led to a paradigm shift in our understanding of the functional diversity of neutrophils. These studies highlight that neutrophils have emerged as key components of the tumor microenvironment, where they can play a dual role in promoting and suppressing cancer. Moreover, several approaches to therapeutically target neutrophils have emerged, and clinical trials are investigating their efficacy. In this review, we discussed the involvement of neutrophils in cancer initiation and progression. We summarized recent advances in therapeutic strategies targeting neutrophils and, most importantly, suggested future research directions that could facilitate the manipulation of neutrophils for therapeutic purposes in cancer patients.

Cancer is the second leading cause of death among humans worldwide. Despite remarkable improvements in cancer therapies, drug resistance remains a significant challenge. The tumor microenvironment (TME) is intimately associated with therapeutic resistance. Tumor‑associated neutrophils (TANs) are a crucial component of the TME, which, along with other immune cells, play a role in tumorigenesis, development and metastasis. In the current review, the roles of TANs in the TME, as well as the mechanisms of neutrophil‑mediated resistance to cancer therapy, including immunotherapy, chemotherapy, radiotherapy and targeted therapy, were summarized. Furthermore, strategies for neutrophil therapy were discussed and TANs were explored as potential targets for cancer treatment. In conclusion, the need to explore the precise roles, recruitment pathways and mechanisms of action of TANs was highlighted for the purpose of developing therapies that precisely target TANs and reverse drug resistance.

Significant sex disparities have been observed in cancer incidence, treatment response to immunotherapy, and susceptibility to adverse effects, affecting both reproductive and non-reproductive organ cancers. While lifestyle factors, carcinogenic exposure, and healthcare access contribute to these disparities, they do not fully explain the observed male-female variation in anti-tumor immunity. Despite the preferential expression of sex hormone receptors in immune cells, X chromosome also contains numerous genes involved in immune function, and its incomplete inactivation may enhance anti-tumor immune responses in females. In contrast, loss or downregulation of Y-linked genes in males has been associated with an increased cancer risk. Additionally, estrogen, progesterone and androgen signaling pathways influence both innate and adaptive immune responses, contributing to sex-specific outcomes in cancer progression and therapy. Sex-biased differences are also evident in the epigenetic regulation of gene expression, cellular senescence, microbiota composition, metabolism, and DNA damage response, all of which impact anti-tumor immunity and immunotherapy treatment efficacy. In general, the combination of sex chromosomes, sex hormones, and hormone receptors orchestrates the phenotype and function of various immune cells involved in tumor immunity. However, sex disparity in each specific immune cell are context and environment dependent, considering the preferential expression of hormone receptor in immune cell and sex hormone levels fluctuate significantly across different life stages. This review aims to outline the molecular, cellular, and epigenetic changes in T cells, B cells, NK cells, DCs, neutrophils, and macrophages driven by sex chromosomes and sex hormone signaling. These insights may inform the design of sex-specific targeted therapies and leading to more individualized cancer treatment strategies.

Tumor-associated neutrophils (TANs) play a critical role in modulating immune responses and exhibit significant heterogeneity. Our previous study demonstrated that jagged canonical Notch ligand 2 (JAG2)+ TANs were associated with an immunosuppressive microenvironment in high-grade serous ovarian cancer (HGSOC), but the underlying mechanism remains unclear. This study aimed to elucidate the role of JAG2+ TANs in tumor immunosuppressive microenvironment in HGSOC.

HGSOC samples were collected, with 274 samples constituting two independent cohorts (training and validation cohorts) and an additional 30 samples utilized to establish patient-derived tumor organoids (PDTOs). We characterized the number and phenotype of JAG2+ TANs by multiplex immunohistochemistry, flow cytometry, and single-cell RNA sequencing (scRNA-seq). We investigated the biological functions of JAG2 in immune evasion using in vitro co-culture systems, flow cytometry, tumor-bearing mouse models, and PDTOs.

JAG2+ TANs expressed elevated levels of immunosuppressive molecules, including programmed cell death ligand 1 and CD14, and had independent prognostic value for the overall survival of patients with HGSOC. scRNA-seq analysis revealed that JAG2+ TANs exhibited a terminally mature phenotype. The infiltration of JAG2+ TANs was positively correlated with the abundance of effector regulatory T cells (eTregs). Interaction with JAG2+ TANs skewed CD4+ T cells towards an eTreg phenotype, a process that was suppressed by the Notch inhibitor LY3039478 and induced by recombinant Jagged2. Furthermore, we demonstrated that JAG2+ TANs enhanced Notch signaling activation, ultimately promoting recombination signal binding protein for immunoglobulin kappa J region (RBPJ)-induced differentiation of naïve CD4+ T cells into eTregs. Clinically, JAG2+ TANs could serve as a biomarker for assessing immunotherapy resistance in various solid tumors. Pharmacological targeting of Notch signaling with LY3039478 or JAG2 neutralization antibodies enhanced the efficacy of programmed cell death protein 1 (PD-1) monoclonal antibodies (mAbs) in both xenograft and PDTO models.

The emergence of JAG2+ TANs is crucial for the differentiation of eTregs, which triggers immune evasion and resistance to anti-PD-1 therapy. Inhibiting Notch signaling with LY3039478 or JAG2 neutralization antibodies may overcome this anti-PD-1 resistance in HGSOC.

Tumor-associated neutrophils (TANs) are important components of the colorectal cancer (CRC) microenvironment. However, their role in CRC remains controversial. This study aimed to assess the prognostic value of TANs in patients with CRC.

We searched the PubMed, EMBASE, and Cochrane Library databases for eligible studies published until January 9, 2023. The pooled hazard ratios (HRs) and odds ratios (ORs) with their 95% confidence intervals (95% CI) were calculated with a random-effects model to assess survival outcomes and clinicopathological features. Subgroup analyses were further conducted to identify potential sources of heterogeneity. Funnel plots and Egger's test were used to measure publication bias.

A total of 19 studies with 7721 patients were included in this meta-analysis. The pooled analysis indicated that high peritumoral TAN infiltration in CRC tissue was significantly associated with favorable cancer-specific survival (HR = 0.57; 95% CI: 0.38-0.86; p = 0.007), but not with overall survival or disease-free survival. No association between high intratumoral or unclear compartment TAN infiltration and CRC prognosis was found. Subgroup analyses showed that the association between TANs and the prognosis of CRC patients differed according to antibody types, tumor stage, quantitative methods, and follow-up time. High intratumoral TAN infiltration was significantly associated with histology type, whereas high TAN infiltration in an unclear compartment was significantly associated with gender, tumor location, and the primary tumor site.

High TAN infiltration, especially in the peritumoral compartment, could be a potential prognostic marker in CRC. More high-quality studies are required to explore its specific prognostic value in CRC.

Neutrophils, the most abundant myeloid cells in human peripheral blood, serve as the first defense line against infection and are also significantly involved in the initiation and progression of cancer. In colorectal cancer (CRC), neutrophils exhibit a dual function by promoting tumor events and exerting antitumor activity, which is related to the heterogeneity of neutrophils. The neutrophil extracellular traps (NETs), gut microbiota, and various cells within the tumor microenvironment (TME) are involved in shaping the heterogeneous function of neutrophils. This article provides an updated overview of the complex functions and underlying mechanisms of neutrophils in CRC and their pivotal role in guiding prognosis assessment and therapeutic strategies, aiming to offer novel insights into neutrophil-associated treatment approaches for CRC.

Rationale: High neutrophil infiltration in hepatocellular carcinoma (HCC) is associated with a poor prognosis in patients with HCC. Tumor-derived exosomes (TDEs) have been proven to be important in the reprogramming of tumor-associated neutrophils (TANs), but the roles and mechanisms have not been fully clarified. Methods: The roles of HCC-exosome-reprogrammed neutrophils on tumor progression were evaluated in the DEN/CCl4-induced HCC mouse model by blocking neutrophil infiltration, depleting neutrophil, and neutrophil adoptive transfer. Transcriptome sequencing and flow cytometry were performed to investigate the effects of HCC exosomes on the phenotype and function of neutrophils. The mobilization and apoptosis of neutrophils were evaluated by the Transwell experiment and Annexin V/7-AAD staining, respectively. Moreover, we detected the effects of HCC-exosome-reprogrammed neutrophils on T cells by flow cytometry. Next, we used the NF-κB pathway inhibitor JSH-23 and miR-362-5p inhibitor or mimic to determine the molecular mechanisms. Lastly, we constructed the miR-362-5p sponge to validate its targeted therapeutic potential. Results: We found that HCC exosomes induced neutrophil infiltration and T-cell exhaustion in the livers of DEN/CCl4-induced HCC mice and promoted tumor progression. Blocking neutrophil infiltration and depleting neutrophils diminished these promotive effects of HCC exosomes. In addition, HCC exosome-reprogrammed neutrophils display proinflammatory and protumor phenotypes, and can directly induce T-cell exhaustion in vitro. The transfer of HCC exosome-reprogrammed neutrophils exacerbated tumor progression and induced T-cell exhaustion, as evidenced by the downregulation of IFN-γ and TNF-α, and the upregulation of PD-1 and Tim3 in T cells. Mechanistically, we found that HCC exosomes upregulate the expression of miR-362-5p in neutrophils and activate the NF-κB signaling pathway by targeting CYLD, promoting the survival and recruitment of neutrophils. In HCC mice, blocking miR-362-5p suppressed neutrophil infiltration, attenuated T-cell exhaustion, and suppressed HCC progression. Conclusions: This study clarified the roles of HCC exosomes on neutrophil infiltration and reprogramming and identified a potential target miR-362-5p for HCC treatment.

Immune checkpoint inhibition (ICI) has revolutionized treatment for metastasized melanoma, but many patients remain unresponsive. Concerning potential adverse events, reliable biomarkers to predict ICI response are needed. In this context, neutrophil-to-lymphocyte ratio (NLR) and derived NLR (dNLR) have emerged. Liver metastases also limit ICI efficacy, correlating with diminished overall survival (OS) and progression-free survival (PFS) and may siphon activated T cells from the systemic circulation, creating an 'immune desert state'. We evaluated the predictive role of NLR and dNLR for ICI response and the impact of liver metastases on systemic immunity and treatment efficacy.

In this single-center retrospective study, we included 141 stage IV melanoma patients undergoing ICI. NLR and dNLR were calculated from absolute neutrophil count, absolute lymphocyte count, and white blood cell count.

Elevated NLR and dNLR were associated with poor response to ICI and inferior PFS. Patients with liver metastases exhibited higher NLR and dNLR levels and showed diminished response to ICI.

Elevated baseline NLR and dNLR predict poor response to ICI and PFS in stage IV melanoma. Liver metastases are negative predictors for ICI response, with associated higher NLR and dNLR levels potentially contributing to therapy resistance.

T-cell receptor (TCR) sequencing provides a novel platform for insight into and characterization of intricate T-cell profiles, advancing the understanding of tumor immune heterogeneity. Recently, transarterial chemoembolization (TACE) combined with systemic therapy has become the recommended regimen for advanced hepatocellular carcinoma. The regulation of the immune microenvironment after TACE and its impact on tumor progression and recurrence has been a focus of research. By examining and tracking fluctuations in the TCR repertoire following combination treatment, novel perspectives on the modulation of the tumor microenvironment post-TACE and the underlying mechanisms governing tumor progression and recurrence can be gained. Clarifying the distinctive metrics and dynamic alterations of the TCR repertoire within the context of combination therapy is imperative for understanding the mechanisms of anti-tumor immunity, assessing efficacy, exploiting novel treatments, and further advancing precision oncology in the treatment of hepatocellular carcinoma. In this review, we initially summarized the fundamental characteristics of TCR repertoire and depicted immune microenvironment remodeling after TACE. Ultimately, we illustrated the prospective applications of TCR repertoires in TACE combined with systemic therapy.

Neutrophils, the most abundant circulating white blood cells, are essential for the initial immune response to infection and injury. Emerging research reveals a dualistic function of neutrophils in cancer, where they can promote or inhibit tumor progression. This dichotomy is influenced by the tumor microenvironment, with neutrophils capable of remodeling the extracellular matrix, promoting angiogenesis, or alternatively inducing cancer cell death and enhancing immune responses. An intriguing yet poorly understood aspect of neutrophil-cancer interactions is the phenomenon of neutrophil engulfment by cancer cells, which has been observed across various cancers. This process, potentially mediated by LC3-associated phagocytosis (LAP), raises questions about whether it serves as a mechanism for immune evasion or contributes to tumor cell death through pathways like ferroptosis. This review examines current knowledge on neutrophil development, their roles in cancer, and the mechanisms of LAP in neutrophil engulfment by tumor cells. We discuss how manipulating LAP impacts cancer progression and may represent a therapeutic strategy. We also explore neutrophils' potential as delivery vehicles for cancer therapeutic agents. Understanding the complex functions of tumor-associated neutrophils (TANs) and the molecular mechanisms underlying LAP in cancer may open new avenues for effective therapeutic interventions and mitigate potential risks.

Tumor-associated neutrophils (TANs) are heterogeneous; thus, their roles in tumor development could vary depending on the cancer type. Here, we showed that TANs affect metabolic dysfunction-associated steatohepatitis hepatocellular carcinoma (MASH-related HCC) more than viral-associated HCC. We attributed this difference to the predominance of SiglecFhi TANs in MASH-related HCC tumors. Linoleic acid and GM-CSF, which are commonly elevated in the MASH-related HCC microenvironment, fostered the development of this c-Myc-driven TAN subset. Through TGFβ secretion, SiglecFhi TANs promoted HCC stemness, proliferation, and migration. Importantly, SiglecFhi TANs supported immune evasion by directly suppressing the antigen presentation machinery of tumor cells. SiglecFhi TAN removal increased the immunogenicity of a MASH-related HCC model and sensitized it to immunotherapy. Likewise, a high SiglecFhi TAN signature was associated with poor prognosis and immunotherapy resistance in HCC patients. Overall, our study highlights the importance of understanding TAN heterogeneity in cancer to improve therapeutic development.

We investigated a novel cancer immunotherapy strategy that effectively suppresses tumor growth in multiple solid tumor models and significantly extends the lifespan of tumor-bearing mice by introducing pathogen antigens into tumors via mRNA-lipid nanoparticles. The pre-existing immunity against the pathogen antigen can significantly enhance the efficacy of this approach. In mice previously immunized with BNT162b2, an mRNA-based COVID-19 vaccine encoding the spike protein of the SARS-CoV-2 virus, intratumoral injections of the same vaccine efficiently tagged the tumor cells with mRNA-expressed spike protein. This action rapidly mobilized the pre-existing memory immunity against SARS-CoV-2 to kill the cancer cells displaying the spike protein, while concurrently reprogramming the tumor microenvironment (TME) by attracting immune cells. The partial elimination of tumor cells in a normalized TME further triggered extensive tumor antigen-specific T cell responses through antigen spreading, eventually resulting in potent and systemic tumor-targeting immune responses. Moreover, combining BNT162b2 treatment with anti-PD-L1 therapy yielded a more substantial therapeutic impact, even in "cold tumor" types that are typically less responsive to treatment. Given that the majority of the global population has acquired memory immunity against various pathogens through infection or vaccination, we believe that, in addition to utilizing the widely held immune memory against SARS-CoV-2 via COVID-19 vaccine, mRNA vaccines against other pathogens, such as Hepatitis B Virus (HBV), Common Human Coronaviruses (HCoVs), and the influenza virus, could be rapidly transitioned into clinical use and holds great promise in treating different types of cancer. The extensive selection of pathogen antigens expands therapeutic opportunities and may also overcome potential drug resistance.

Neutrophils are key mediators of the immune response and play essential roles in the development of tumors and immune evasion. Emerging studies indicate that neutrophils also play a critical role in the immunotherapy resistance in cancer. In this review, firstly, we summarize the novel classification and phenotypes of neutrophils and describe the regulatory relationships between neutrophils and tumor metabolism, flora microecology, neuroendocrine and tumor therapy from a new perspective. Secondly, we review the mechanisms by which neutrophils affect drug resistance in tumor immunotherapy from the aspects of the immune microenvironment, tumor antigens, and epigenetics. Finally, we propose several promising strategies for overcoming tumor immunotherapy resistance by targeting neutrophils and provide new research ideas in this area.

Exhausted T cell (Tex) is a specific state of T cell dysfunction, in which these T cells gradually lose their effector function and change their phenotype during chronic antigen stimulation. The enrichment of exhausted CD8+ T cell (CD8+ Tex) in the tumor microenvironment is one of the important reasons leading to the poor efficacy of immunotherapy. Recent studies have reported many reasons leading to the CD8+ T cell exhaustion. In addition to cancer cells, myeloid cells can also contribute to T cell exhaustion via many ways. In this review, we discuss the history of the concept of exhaustion, CD8+ T cell dysfunction states, the heterogeneity, origin, and characteristics of CD8+ Tex. We then focus on the effects of myeloid cells on CD8+ Tex, including tumor-associated macrophages (TAMs), dendritic cells (DCs) and neutrophils. Finally, we systematically summarize current strategies and recent advancements in therapies reversing and CD8+ T cell exhaustion.

The tumor microenvironment (TME) is closely associated with the therapeutic response and clinical outcome of cancer drug therapies, which mainly include immunotherapy, chemotherapy and targeted therapy. Neutrophils that infiltrate tumors, also known as tumor-associated neutrophils (TANs), constitute a primary part of the TME. However, the functional importance of TANs in cancer drug therapy has long been overlooked because of their relatively short life span. Recent studies have shown that TANs play crucial protumoral or antitumoral roles in cancer drug treatment, largely because of their diversity and plasticity. This review describes the development, heterogeneity and recruitment of neutrophils in the context of cancer and emphasizes the role and mechanisms of TANs in cancer drug resistance. Additionally, several potential neutrophil-targeted strategies are discussed.

Neutrophils, the most abundant leukocyte population in circulation, play a crucial role in detecting and responding to foreign cells, such as pathogens and tumor cells. However, the impact of neutrophils on cancer pathogenesis has been overlooked because of their short lifespan, terminal differentiation, and limited transcriptional activity. Within the tumor microenvironment (TME), neutrophils can be influenced by tumor cells or other stromal cells to acquire either protumor or antitumor properties via the cytokine environment. Despite progress in neutrophil-related research, a comprehensive understanding of tissue-specific neutrophil diversity and adaptability in the TME is still lacking, which poses a significant obstacle to the development of neutrophil-based cancer therapies. This review evaluated the current studies on the dual roles of neutrophils in cancer progression, emphasizing their importance in predicting clinical outcomes, and explored various approaches for targeting neutrophils in cancer treatment, including their potential synergy with cancer immunotherapy.

Microbial systems have been synthetically engineered to deploy therapeutic payloads in vivo1,2. With emerging evidence that bacteria naturally home in on tumours3,4 and modulate antitumour immunity5,6, one promising application is the development of bacterial vectors as precision cancer vaccines2,7. Here we engineered probiotic Escherichia coli Nissle 1917 as an antitumour vaccination platform optimized for enhanced production and cytosolic delivery of neoepitope-containing peptide arrays, with increased susceptibility to blood clearance and phagocytosis. These features enhance both safety and immunogenicity, achieving a system that drives potent and specific T cell-mediated anticancer immunity that effectively controls or eliminates tumour growth and extends survival in advanced murine primary and metastatic solid tumours. We demonstrate that the elicited antitumour immune response involves recruitment and activation of dendritic cells, extensive priming and activation of neoantigen-specific CD4+ and CD8+ T cells, broader activation of both T and natural killer cells, and a reduction of tumour-infiltrating immunosuppressive myeloid and regulatory T and B cell populations. Taken together, this work leverages the advantages of living medicines to deliver arrays of tumour-specific neoantigen-derived epitopes within the optimal context to induce specific, effective and durable systemic antitumour immunity.

Given the significant advancements in the management of hepatocellular carcinoma (HCC) and the emergence of novel treatment approaches, establishing reliable predictors has become crucial for optimizing patient selection and therapeutic sequencing in HCC. In this study, we aimed to investigate the prognostic factors and treatment efficacy associated with lenvatinib-based therapy.

We retrospectively enrolled 53 patients receiving lenvatinib monotherapy, and 19 patients receiving lenvatinib plus immune checkpoint inhibitor combination therapy as their first-line systemic treatment for unresectable HCC at a single medical center. We employed univariate and multivariate Cox regression analyses to ascertain the factors influencing survival in these cohorts.

For lenvatinib monotherapy and the combination therapy, the objective response rates were 30.2% and 63.2%, respectively (P=0.03); the median progression-free survival (PFS) durations were 7 months [95% confidence interval (CI): 4.5-9.5] and 12 months (95% CI: 6.4-17.6), respectively (P=0.74); and the median overall survival (OS) was not reached in either group (P=0.93). Although patients receiving the combination therapy had a greater treatment response, no significant survival differences were observed between the lenvatinib monotherapy and combination therapy subgroups, even after inverse probability of treatment weighting (IPTW). Patients who received lenvatinib monotherapy could be stratified based on a combination of albumin-bilirubin (ALBI) grade (either grade 1 or 2a) and a neutrophil-lymphocyte ratio (NLR) of ≤5.8. Compared to the other subgroups combined, those who met both of these criteria exhibited PFS with a hazard ratio (HR) of 0.382 (95% CI: 0.168-0.871; P=0.02), corresponding to 11 and 5 months, respectively; and an OS (HR: 0.198, 95% CI: 0.043-0.920; P=0.04) of not reached versus 12 months, respectively, according to multivariate Cox regression analysis.

In our study cohort, there were no statistically significant differences observed in the survival rates between patients treated with lenvatinib monotherapy and those treated with a combination of lenvatinib and immunotherapy. The incorporation of ALBI grade and NLR facilitates the stratification of survival outcomes in patients with unresectable HCC undergoing lenvatinib monotherapy.

Neutrophils have long been consistently adjudged to hold a dominant position in acute inflammation, which once led people to undervalue their role in chronic malignancy. It is now acknowledged that neutrophils also infiltrate into the tumor microenvironment in substantial quantities and form a highly abundant immune population within the tumor, known as tumor-associated neutrophils (TANs). There has been a surge of interest in researching the eminent heterogeneity and plasticity of TANs in recent years, and scholars increasingly cotton on to the multifaceted functions of TANs so that strenuous endeavors have been devoted to enunciating their potential as therapeutic targets. Yet it remains much left to translate TAN-targeted immunotherapies into clinical practice. Therefore, there is great significance to comprehensively appraise the research status, focal point, and evolution trend of TAN by using bibliometric analysis.

Publications related to TAN research from 2000 to 2024 are extracted from the Web of Science Core Collection. Bibliometric analysis and visualization were performed by tools encompassing Microsoft Excel, VOSviewer, CiteSpace, R-bibliometrix, and so on.

The bibliometric analysis included a total of 788 publications authored by 5291 scholars affiliated with 1000 institutions across 58 countries/regions, with relevant articles published in 324 journals. Despite China's maximum quantity of publications and top 10 institutions, the United States is the leading country with the most high-quality publications and is also the global cooperation center. FRONTIERS IN IMMUNOLOGY published the most papers, whereas CANCER RESEARCH is the highest co-cited journal. Israeli professor Fridlender, Zvi G. is the founder, pioneer, and cultivator with the highest citation counts and H-index in the TAN area. Our analysis prefigures the future trajectories: TAN heterogeneity, neutrophil extracellular trap, the crosstalk between TANs and immunocytes, and immunotherapy will likely be the focus of future research.

A comprehensive bibliometric and visual analysis is first performed to map the current landscape and intellectual structure of TAN, which proffers fresh perspectives for further research. The accurate identification of distinct TAN subpopulations and the precise targeting of key pro-tumor/anti-tumor subpopulations hold immense potential to develop into a TAN-targeted immunotherapy.

Since differentiating malignant ascites from benign ascites has always been a clinical difficult, recognition of novel biomarkers in malignant ascites of hepatocellular carcinoma (HCC) patients could be helpful for establishing a diagnosis for HCC patients with ascitic fluids.

Thirty-five HCC patients with malignant ascites and chronic liver diseases patients with benign ascites were enrolled. Serum and ascites specimens were collected to determine TAN subpopulations and NETs concentration. Then, the correlation between ascitic NETs levels and clinical features were analyzed, and ROC curves were generated to evaluate the diagnostic value of NETs. For in vitro study, fresh neutrophils were employed to explore the underlying mechanism of TAN polarization and NETs formation using RNAseq analysis.

Significantly increased pro-tumor PD-L1+ TANs and higher lactate levels were measured in HCC ascites. RNAseq data showed that lactate regulated genes expression involving PD-L1 expression and NETs formation, suggesting that ascitic lactate might be responsible for tumor progression in TME. Then, NETs-related markers including calprotectin, dsDNA, CitH3, MPO and MPO-DNA were found dramatically elevated in malignant ascites. Next, correlation analysis revealed that ascitic NETs levels positively correlated with LDH, a classic ascitic biochemical indicator. Furthermore, we identified the diagnostic values of NETs in discriminating malignant ascites from benign ascites.

Our findings highlighted that elevated ascitic NETs served as a biomarker in HCC patients with malignant ascites, which provided useful insights for both clinical and basic research for malignant ascites diagnosis and management.

Neutrophilic cells are among the most abundant immune populations within the head and neck tumor microenvironment (TME) and harbor multiple mechanisms of immunosuppression. Despite these important features, neutrophilic cells may be underrepresented in contemporary studies that aim to comprehensively characterize the immune landscape of the TME due to discrepancies in tissue processing and analysis techniques. Here, we review the role of pathologically activated neutrophilic cells within the TME and pitfalls of various approaches used to study their frequency and function in clinical samples.

The literature was identified by searching PubMed for "immune landscape" and "tumor immune microenvironment" in combination with keywords describing solid tumor malignancies. Key publications that assessed the immune composition of solid tumors derived from human specimens were included. The tumor and blood processing methodologies in each study were reviewed in depth and correlated with the reported abundance of neutrophilic cells.

Neutrophilic cells do not survive cryopreservation, and many studies fail to identify and study neutrophilic cell populations due to cryopreservation of clinical samples for practical reasons. Additional single-cell transcriptomic studies filter out neutrophilic cells due to low transcriptional counts.

This report can help readers critically interpret studies aiming to comprehensively study the immune TME that fail to identify and characterize neutrophilic cells.

Tumor relapse and metastasis are the major causes of mortality associated with urothelial cancer. In the tumor microenvironment, negative regulatory molecules and various immune cell subtypes suppress antitumor immunity. The inflammatory microenvironment, associated with neutrophils and neutrophil extracellular traps (NETs), promotes tumor metastasis. However, no drugs are currently available to specifically inhibit neutrophils and NETs. In this study, we first demonstrated that icaritin (ICT), a Chinese herbal remedy that is a first-line treatment for advanced and incurable hepatocellular carcinoma, reduces NETs caused by suicidal NETosis and prevents neutrophil infiltration in the tumor microenvironment. Mechanistically, ICT binds to and inhibits the expression of PADI2 in neutrophils, thereby suppressing PADI2-mediated histone citrullination. Moreover, ICT inhibits ROS generation, suppresses the MAPK signaling pathway, and inhibits NET-induced tumor metastasis. Simultaneously, ICT inhibits tumoral PADI2-mediated histone citrullination, which consequently suppresses the transcription of neutrophil-recruiting genes such as GM-CSF and IL-6. The downregulation of IL-6 expression, in turn, forms a regulatory feedback loop through the JAK2/STAT3/IL-6 axis. Through a retrospective study of clinical samples, we found a correlation between neutrophils, NETs, UCa prognosis, and immune evasion. Combining ICT with immune checkpoint inhibitors may have synergistic effects. In summary, our study demonstrated that ICT could be a novel inhibitor of NETs and a novel UCa treatment.

Adoptive transfer of tumor infiltrating lymphocytes (TIL therapy) has proven highly effective for treating solid cancers, including non-small cell lung cancer (NSCLC). However, not all patients benefit from this therapy for yet unknown reasons. Defining markers that correlate with high tumor-reactivity of the autologous TIL products is thus key for achieving better tailored immunotherapies. We questioned whether the composition of immune cell infiltrates correlated with the tumor-reactivity of expanded TIL products. Unbiased flow cytometry analysis of immune cell infiltrates of 26 early-stage and 20 late-stage NSCLC tumor lesions was used for correlations with the T cell differentiation and activation status, and with the expansion rate and anti-tumor response of generated TIL products. The composition of tumor immune infiltrates was highly variable between patients. Spearman's Rank Correlation revealed that high B cell infiltration negatively correlated with the tumor-reactivity of the patient's expanded TIL products, as defined by cytokine production upon exposure to autologous tumor digest. In-depth analysis revealed that tumor lesions with high B cell infiltrates contained tertiary lymphoid structure (TLS)-related immune infiltrates, including BCL6+ antibody-secreting B cells, IgD+BCL6+ B cells and CXCR5+BLC6+ CD4+ T cells, and higher percentages of naïve CD8+ T cells. In conclusion, the composition of immune cell infiltrates in NSCLC tumors associates with the functionality of the expanded TIL product. Our findings may thus help improve patient selection for TIL therapy.

Immune escape is an important feature of hepatocellular carcinoma (HCC). The overall response rate of immune checkpoint inhibitors (ICIs) in HCC is still limited. Revealing the immune regulation mechanisms and finding new immune targets are expected to further improve the efficacy of immunotherapy. Our study aims to use CRISPR screening mice models to identify potential targets that play a critical role in HCC immune evasion and further explore their value in improving immunotherapy.

We performed CRISPR screening in two mice models with different immune backgrounds (C57BL/6 and NPG mice) and identified the immunosuppressive gene Gsk3a as a candidate for further investigation. Flow cytometry was used to analyze the impact of Gsk3a on immune cell infiltration and T-cell function. RNA sequencing was used to identify the changes in neutrophil gene expression induced by Gsk3a and alterations in downstream molecules. The therapeutic value of the combination of Gsk3a inhibitors and anti-programmed cell death protein-1 (PD-1) antibody was also explored.

Gsk3a, as an immune inhibitory target, significantly promoted tumor growth in immunocompetent mice rather than immune-deficient mice. Gsk3a inhibited cytotoxic T lymphocytes (CTLs) function by inducing neutrophil chemotaxis. Gsk3a promoted self-chemotaxis of neutrophil expression profiles and neutrophil extracellular traps (NETs) formation to block T-cell activity through leucine-rich α-2-glycoprotein 1 (LRG1). A significant synergistic effect was observed when Gsk3a inhibitor was in combination with anti-PD-1 antibody.

We identified a potential HCC immune evasion target, Gsk3a, through CRISPR screening. Gsk3a induces neutrophil recruitment and NETs formation through the intermediate molecule LRG1, leading to the inhibition of CTLs function. Targeting Gsk3a can enhance CTLs function and improve the efficacy of ICIs.

Hepatocellular carcinoma (HCC) is a highly heterogeneous malignancy with high incidence, recurrence, and metastasis rates. The emergence of immunotherapy has improved the treatment of advanced HCC, but problems such as drug resistance and immune-related adverse events still exist in clinical practice. The immunosuppressive tumor microenvironment (TME) of HCC restricts the efficacy of immunotherapy and is essential for HCC progression and metastasis. Therefore, it is necessary to elucidate the mechanisms behind immunosuppressive TME to develop and apply immunotherapy. This review systematically summarizes the pathogenesis of HCC, the formation of the highly heterogeneous TME, and the mechanisms by which the immunosuppressive TME accelerates HCC progression and metastasis. We also review the status of HCC immunotherapy and further discuss the existing challenges and potential therapeutic strategies targeting immunosuppressive TME. We hope to inspire optimizing and innovating immunotherapeutic strategies by comprehensively understanding the structure and function of immunosuppressive TME in HCC.

The colon is the largest compartment of the immune system, with innate immune cells exposed to antigens in the environment. However, the mechanisms by which the innate immune system is instigated are poorly defined in colorectal cancer (CRC). Here, a population of CD16+ neutrophils that specifically accumulate in CRC tumor tissues by imaging mass cytometry (IMC), immune fluorescence, and flow cytometry, which demonstrated pro-tumor activity by disturbing natural killer (NK) cells are identified. It is found that these CD16+ neutrophils possess abnormal cholesterol accumulation due to activation of the CD16/TAK1/NF-κB axis, which upregulates scavenger receptors for cholesterol intake including CD36 and LRP1. Consequently, these region-specific CD16+ neutrophils not only competitively inhibit cholesterol intake of NK cells, which interrupts NK lipid raft formation and blocks their antitumor signaling but also release neutrophil extracellular traps (NETs) to induce the death of NK cells. Furthermore, CD16-knockout reverses the pro-tumor activity of neutrophils and restored NK cell cytotoxicity. Collectively, the findings suggest that CRC region-specific CD16+ neutrophils can be a diagnostic marker and potential therapeutic target for CRC.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy characterized by a dismal five-year survival rate of less than 10%. Neutrophils are key components of the innate immune system, playing a pivotal role in the PDAC immune microenvironment.

This review provides a comprehensive survey of the pivotal involvement of neutrophils in the tumorigenesis and progression of PDAC. Furthermore, it synthesizes preclinical and clinical explorations aimed at targeting neutrophils within the milieu of PDAC, subsequently proposing a conceptual framework to propel further inquiry focused on enhancing the therapeutic efficacy of PDAC through neutrophil-targeted strategies. PubMed and Web of Science databases were utilized for researching neutrophils in pancreatic cancer publications prior to 2024.

Neutrophils play roles in promoting tumor growth and metastasis in PDAC and are associated with poor prognosis. However, the heterogeneity and plasticity of neutrophils and their complex relationships with other immune cells and extracellular matrix also provide new insights for immunotherapy targeting neutrophils to achieve a better prognosis for PDAC.

Lung cancer is the most common cause of cancer-related death in both males and females in the U.S. and non-small-cell lung cancer (NSCLC) accounts for 85%. Although the use of first- or second-line immune checkpoint inhibitors (ICIs) exhibits remarkable clinical benefits, resistance to ICIs develops over time and dampens the efficacy of ICIs in patients. Tumor-associated neutrophils (TANs) have an important role in modulating the tumor microenvironment (TME) and tumor immune response. The major challenge in the field is to characterize the TANs in NSCLC TME and understand the link between TAN-related immunosuppression with ICI treatment response. In this review, we summarize the current studies of neutrophil interaction with malignant cells, T-cells, and other components in the TME. Ongoing clinical trials are aimed at utilizing reagents that have putative effects on tumor-associated neutrophils, in combination with ICI. Elevated neutrophil populations and neutrophil-associated factors could be potential therapeutic targets to enhance anti-PD1 treatment in NSCLC.

Breast cancer (BC) is currently the most common malignant tumour in women and one of the leading causes of their death around the world. New and increasingly personalised diagnostic and therapeutic tools have been introduced over the last few decades, along with significant advances regarding the study and knowledge related to BC. The tumour microenvironment (TME) refers to the tumour cell-associated cellular and molecular environment which can influence conditions affecting tumour development and progression. The TME is composed of immune cells, stromal cells, extracellular matrix (ECM) and signalling molecules secreted by these different cell types. Ever deeper understanding of TME composition changes during tumour development and progression will enable new and more innovative therapeutic strategies to become developed for targeting tumours during specific stages of its evolution. This review summarises the role of BC-related TME components and their influence on tumour progression and the development of resistance to therapy. In addition, an account on the modifications in BC-related TME components associated with therapy is given, and the completed or ongoing clinical trials related to this topic are presented.

Pancreatic cancer (PC) is a highly malignant tumour of the digestive system with poor therapeutic response and low survival rates. Immunotherapy has rapidly developed in recent years and has achieved significant outcomes in numerous malignant neoplasms. However, responses to immunotherapy in PC are rare, and the immunosuppressive and desmoplastic tumour microenvironment (TME) significantly hinders their efficacy in PC. Tumour-associated neutrophils (TANs) play a crucial role in the PC microenvironment and exert a profound influence on PC immunotherapy by establishing a robust stromal shelter and restraining immune cells to assist PC cells in immune escape, which may subvert the current status of PC immunotherapy. The present review aims to offer a comprehensive summary of the latest progress in understanding the involvement of TANs in PC desmoplastic and immunosuppressive functions and to emphasise the potential therapeutic implications of focusing on TANs in the immunotherapy of this deleterious disease. Finally, we provide an outlook for the future use of TANs in PC immunotherapy.

Neutrophils can be beneficial or deleterious during tuberculosis (TB). Based on the expression of MHC-II and programmed death ligand 1 (PD-L1), we distinguished two functionally and transcriptionally distinct neutrophil subsets in the lungs of mice infected with mycobacteria. Inflammatory [MHC-II-, PD-L1lo] neutrophils produced inflammasome-dependent IL-1β in the lungs in response to virulent mycobacteria and "accelerated" deleterious inflammation, which was highly exacerbated in IFN-γR-/- mice. Regulatory [MHC-II+, PD-L1hi] neutrophils "brake" inflammation by suppressing T-cell proliferation and IFN-γ production. Such beneficial regulation, which depends on PD-L1, is controlled by IFN-γR signaling in neutrophils. The hypervirulent HN878 strain from the Beijing genotype curbed PD-L1 expression by regulatory neutrophils, abolishing the braking function and driving deleterious hyperinflammation in the lungs. These findings add a layer of complexity to the roles played by neutrophils in TB and may explain the reactivation of this disease observed in cancer patients treated with anti-PD-L1.

Hepatocellular carcinoma is a common and highly lethal tumour. The tumour microenvironment (TME) plays an important role in the progression and metastasis of hepatocellular carcinoma (HCC). A cell death mechanism, termed NETosis, has been found to play an important role in the TME of HCC.

This review article focuses on the role of NETosis in the TME of HCC, a novel form of cell death in which neutrophils capture and kill microorganisms by releasing a type of DNA meshwork fibres called "NETs". This process is associated with neutrophil activation, local inflammation and cytokines. The study suggests that NETs play a multifaceted role in the development and metastasis of HCC. The article also discusses the role of NETs in tumour proliferation and metastasis, epithelial-mesenchymal transition (EMT), and surgical stress. In addition, the article discusses the interaction of NETosis with other immune cells in the TME and related therapeutic strategies. A deeper understanding of NETosis can help us better understand the complexity of the immune system and provide a new therapeutic basis for the treatment and prevention of HCC.

In conclusion, NETosis is important in the TME of liver. NETs have been shown to contribute to the progression and metastasis of liver cancer. The interaction between NETosis and immune cells in the TME, as well as related therapies, are important areas of research.

Triple-negative breast cancer is a highly aggressive and heterogeneous breast cancer subtype characterized by early metastasis, poor prognosis, and high recurrence. Targeting histone citrullination-mediated chromatin dysregulation to induce epigenetic alterations shows great promise in TNBC therapy. We report the synthesis, optimization, and evaluation of a novel series of β-carboline-derived peptidyl arginine deiminase 4 inhibitors that exhibited potent inhibition of TNBC cell proliferation. The most outstanding PAD4 inhibitor, compound 28, hindered the PAD4-H3cit-NET signaling pathway and inhibited the growth of solid tumors and pulmonary metastatic nodules in the 4T1 in situ mouse model. Furthermore, 28 improved the tumor immune microenvironment by reshaping neutrophil phenotype, upregulating the proportions of dendritic cells and M1 macrophages, and reducing the amount of myeloid-derived suppressor cells. In conclusion, our work offered 28 as an efficacious PAD4 inhibitor that exerts a combination of conventional chemotherapy and immune-boosting effects, which represents a potential therapy strategy for TNBC.