Tumor-associated macrophages (TAMs) play a multifaceted role in the tumor microenvironment, notably by suppressing antitumor immune responses through immunosuppressive mechanisms. TAMs secrete a range of cytokines that simultaneously inhibit T cell function and foster a microenvironment that supports tumor progression and dissemination. Our study has delved into the intricate relationship between the metabolic reprogramming of TAMs and their impact on tumor progression. Mitochondrial metabolic reprogramming mediated by the SENP1-Sirt3 axis altered the dynamics and activity of tumor-infiltrating immune cells, including macrophages and CD8+ T lymphocytes. SENP1-Sirt3 axis increases the level of acetyl-CoA in macrophage mitochondria, which in turn promotes cholesterol biosynthesis in macrophages. The upregulation of cholesterol synthesis is a key factor in driving macrophage polarization towards the immunosuppressive M2 phenotype, which in turn supports tumor development. Notably, increased cholesterol levels contributed to a reduction in the number and activity of CD8+ T cells, which are essential for mounting an effective immune response against cancer cells. These findings suggest that targeting cholesterol biosynthesis in TAMs may be a promising strategy for cancer immunotherapy. SIGNIFICANCE: Activation of the SENP1-Sirt3 axis initiates mitochondrial metabolic reprogramming in tumor-associated macrophages (TAMs), leading to enhanced cholesterol and acetyl-CoA production, M2 macrophage polarization, and impaired CD8+ T cell anti-tumor responses.

Intrahepatic cholangiocarcinoma (ICC) is an aggressive cancer with an extremely poor prognosis, highlighting the urgent need for new treatment options. Recent studies increasingly suggest that the Forkhead box M1 (FOXM1) transcription factor may serve as a candidate target for cancer immunotherapy. However, its role and the underlying molecular mechanisms in ICC remain not fully understood. Here, we identify thiostrepton (TST) as a potent FOXM1 inhibitor, capable of exerting "dual anti-tumor" effects in ICC. On one hand, TST effectively suppresses tumor cell proliferation and metastasis. On the other hand, TST treatment improves the tumor immune microenvironment by reprogramming tumor-associated macrophages (TAMs), thereby enhancing anti-tumor immune responses. Mechanistically, TST directly alleviates ICC progression by arresting the cell cycle, promoting apoptosis, and inhibiting the epithelial-mesenchymal transition (EMT) process. Furthermore, TST-treated tumor cells secrete cytokines that drive TAMs repolarization toward the tumor-suppressive M1 phenotype. Overall, our results indicate that FOXM1 can serve as a novel target for ICC immunotherapy. By targeting FOXM1, TST exerts "dual anti-tumor" effects and has the potential to become a promising immunotherapy agent for ICC patients.

Myeloid cells play a crucial dual role in cancer progression and response to therapy, promoting tumor growth, enabling immune suppression, and contributing to metastatic spread. The ability of these cells to modulate the immune system has made them attractive targets for therapeutic strategies aimed at shifting their function from tumor promotion to fostering antitumor immunity. Therapeutic approaches targeting myeloid cells focus on modifying their numbers, genetics, metabolism, and interactions within the tumor microenvironment. These strategies aim to reverse their suppressive functions and redirect them to support antitumor immune responses by inhibiting immunosuppressive pathways, targeting specific receptors, and promoting their differentiation into less immunosuppressive phenotypes. Here, we discuss recent approaches to clinically target tumor myeloid cells, focusing on reprogramming myeloid cells to promote antitumor immunity.

Colorectal cancer (CRC) is one of the most common malignant tumors of the digestive tract, with increasing incidence and mortality rates, posing a significant burden on human health. Its progression relies on various mechanisms, among which the tumor microenvironment and tumor-associated macrophages (TAMs) have garnered increasing attention. Macrophage infiltration in various solid tumors is associated with poor prognosis and is linked to chemotherapy resistance in many cancers. These significant biological behaviors depend on the heterogeneity of macrophages. Tumor-promoting TAMs comprise subpopulations characterized by distinct markers and unique transcriptional profiles, rendering them potential targets for anticancer therapies through either depletion or reprogramming from a pro-tumoral to an anti-tumoral state. Single-cell RNA sequencing technology has significantly enhanced our research resolution, breaking the traditional simplistic definitions of macrophage subtypes and deepening our understanding of the diversity within TAMs. However, a unified elucidation of the nomenclature and molecular characteristics associated with this diversity remains lacking. In this review, we assess the application of conventional macrophage polarization subtypes in colorectal malignancies and explore several unique subtypes defined from a single-cell omics perspective in recent years, categorizing them based on their potential functions.

Arginine metabolism in tumors is often shunted into the pathway producing pro-tumor and immune suppressive polyamines (PAs), while downmodulating the alternative nitric oxide (NO) synthesis pathway. Aiming to correct arginine metabolism in tumors, arginine deprivation therapy and inhibitors of PA synthesis have been developed. Despite some therapeutic advantages, these approaches have often yielded severe side effects, making it necessary to explore an alternative strategy. We previously reported that supplementing sepiapterin (SEP), the endogenous precursor of tetrahydrobiopterin (BH4, the essential NO synthase cofactor), could correct arginine metabolism in tumor cells and tumor-associated macrophages (TAMs) and induce their metabolic and phenotypic reprogramming. We saw that oral SEP treatment effectively suppressed the growth of HER2-positive mammary tumors in animals. SEP also has no reported dose-dependent toxicity in clinical trials for metabolic disorders. In the present study, we tested our hypothesis that a long-term administration of SEP to individuals susceptible to HER2-positive mammary tumor would protect them against tumor occurrence.

We administered SEP, in comparison to control DMSO, to MMTV-neu mice susceptible to HER2-positive mammary tumors for 8 months starting at their pre-pubertal stage. We monitored tumor onsets to determine the rate of tumor-free survival. After 8 months of treatment, we grouped animals into DMSO treatment with or without tumors and SEP treatment with or without tumors. We analyzed blood metabolites, PBMC, and bone marrow of DMSO vs. SEP treated animals.

We found that a long-term use of SEP in animals susceptible to HER2-positive mammary tumors effectively suppressed tumor occurrence. These SEP-treated animals had undergone reprogramming of the systemic metabolism and immunity, elevating total T cell counts in the circulation and bone marrow. Given that bone marrow-resident T cells are mostly memory T cells, it is plausible that chronic SEP treatment promoted memory T cell formation, leading to a potent tumor prevention.

These findings suggest the possible roles of the SEP/BH4/NO axis in promoting memory T cell formation and its potential therapeutic utility for preventing HER2-positive breast cancer.

Myeloid-derived suppressor cells (MDSCs) are believed to be key promoters of tumor development and are recognized as a hallmark of cancer cells' ability to evade the immune system evasion. MDSC levels often increase in peripheral blood and the tumor microenvironment (TME). These cells exert immunosuppressive functions, weakening the anticancer immune surveillance system, in part by repressing T-cell immunity. Moreover, MDSCs may promote tumor progression and interact with cancer cells, increasing MDSC expansion and favoring an immunotolerant TME. This review analyzes the primary roles of MDSCs in cancer and T-cell immunity, discusses the urgent need to develop effective MDSC-targeted therapies, and highlights the potential synergistic combination of MDSC targeting with chimeric antigen receptors and immune checkpoint inhibitors.

Recent breakthroughs in tumor immunotherapy have confirmed the capacity of the immune system to fight several cancers. The effective means of treating cancer involves accelerating the death of tumor cells and improving patient immunity. Dynamic changes in the tumor immune microenvironment alter the actual effects of anti-tumor drug production and may trigger favorable or unfavorable immune responses by modulating tumor-infiltrating lymphocytes. Notably, CD8+ T cells are one of the primary tumor-infiltrating immune cells that provide anti-tumor response. Tumor cells and tumor stem cells will resist or evade destruction through various mechanisms as CD8+ T cells exert their anti-tumor function. This paper reviews the research on the regulation of tumor development and prognosis by cancer stem cells that directly or indirectly alter the role of tumor-infiltrating CD8+ T cells. We also discuss related immunotherapy strategies.

Lung adenocarcinoma (LUAD) is responsible for majority cases of lung cancer and considered to be the primary cause of cancer-related mortality. The imbalance of cellular proliferation and apoptosis is critically implicated in the pathogenesis and progression of LUAD. Sphingomyelin, a vital lipid component, is integral to the regulation of tumor cell growth and apoptosis, and has garnered significant attention as a target in novel anticancer therapies. The pivotal molecules involved in sphingomyelin metabolism are crucial in modulating tumor cell behavior, thereby influencing clinical outcomes.

A comprehensive consensus clustering analysis was conducted by collecting clinical LUAD figures from the TCGA and GEO databases. By employing Cox regression and Lasso regression analysis, a prognostic model for LUAD patients was established by identifying seven sphingolipid-related genes (SRGs), and validated in the GEO database. The study also delved into the clinical relevance, functional capabilities, and immune implications of prognostic signals associated with sphingolipid metabolism. Finally, experiments conducted in vitro confirmed the imbalance of sphingolipid-associated genes in LUAD.

Using the prognostic model, lung adenocarcinoma (LUAD) patients can be divided into high-risk and low-risk groups. Meanwhile, we can observe marked disparities in survival times among these groups. Additionally, the model demonstrates high predictive accuracy in external validation cohorts. Research on the immune microenvironment and immunotherapy points to this risk stratification as a useful reference for immunotherapeutic strategies in LUAD. Finally, our hypothesis was corroborated through in vitro experiments.

This study demonstrates that sphingolipid-related gene prognostic characteristics correlate with tumor progression and recurrence, long-term prognosis, and immune infiltration in LUAD patients. The outcomes of our study could help shape innovative strategies for early intervention and prognosis prediction in lung adenocarcinoma.

Acute myeloid leukemia (AML) is a highly aggressive hematological malignancy. Traditional chemotherapy methods not only bring serious side effects, but also lead to high recurrence rate and drug resistance in some patients. However, as an emerging therapeutic strategy, immunotherapy has shown great potential in the field of AML treatment in recent years. At present, common immunotherapy methods for AML include monoclonal antibodies, CAR-T cell therapy, and immune checkpoint inhibitors. With the deepening of research and technological progress, especially the application of nanotechnology in medicine, new immunotherapy is expected to become one of the important means for the treatment of acute myeloid leukemia in the future.

Immune cells undergo cytokine-driven polarization in response to diverse stimuli, altering their transcriptional profiles and functional states. This dynamic process is central to immune responses in health and diseases, yet a systematic approach to assess cytokine-driven polarization in single-cell RNA sequencing data has been lacking.

To address this gap, we developed single-cell unified polarization assessment (Scupa), the first computational method for comprehensive immune cell polarization assessment. Scupa leverages data from the Immune Dictionary, which characterizes cytokine-driven polarization states across 14 immune cell types. By integrating cell embeddings from the single-cell foundation model Universal Cell Embeddings, Scupa effectively identifies polarized cells across different species and experimental conditions. Applications of Scupa in independent datasets demonstrated its accuracy in classifying polarized cells and further revealed distinct polarization profiles in tumor-infiltrating myeloid cells across cancers. Scupa complements conventional single-cell data analysis by providing new insights into dynamic immune cell states, and holds potential for advancing therapeutic insights, particularly in cytokine-based therapies.

The code is available at https://github.com/bsml320/Scupa.

Clinical and biological information in large datasets of gene expression across cancers could be tapped with unsupervised deep learning. However, difficulties associated with biological interpretability and methodological robustness have made this impractical. Here we describe an unsupervised deep-learning framework for the generation of low-dimensional latent spaces for gene-expression data from 50,211 transcriptomes across 18 human cancers. The framework, which we named DeepProfile, outperformed dimensionality-reduction methods with respect to biological interpretability and allowed us to unveil that genes that are universally important in defining latent spaces across cancer types control immune cell activation, whereas cancer-type-specific genes and pathways define molecular disease subtypes. By linking latent variables in DeepProfile to secondary characteristics of tumours, we discovered that mutation burden is closely associated with the expression of cell-cycle-related genes, and that the activity of biological pathways for DNA-mismatch repair and MHC class II antigen presentation are consistently associated with patient survival. We also found that tumour-associated macrophages are a source of survival-correlated MHC class II transcripts. Unsupervised learning can facilitate the discovery of biological insight from gene-expression data.

Immune checkpoint plus tyrosine kinase inhibition (IO + TKI) has emerged as the first-line therapy in metastatic renal cell carcinoma (RCC), but no biomarker can predict its efficacy. Thymidine kinase 1 (TK1) is closely associated with immune evasion in tumors.

Metastatic RCC patients treated by IO + TKI were enrolled from two cohorts (ZS-MRCC, n = 45; Javelin-101, n = 726). High-risk localized RCC were also enrolled (ZS-HRRCC, n = 40). TK1 was assessed by RNA-sequencing in all cohorts, and the immune contexture was assessed by flow cytometry and immunohistochemistry.

Higher TK1 expression was found in patients resistant to IO + TKI therapy (p = 0.025). High-TK1 group showed poor progression-free survival (PFS) in both the ZS-MRCC cohort (P = 0.008) and the Javelin-101 cohort (P = 0.036). By multivariate Cox regression, high-TK1 was determined as an independent factor for poor PFS (hazard ratio (HR) = 3.855, P = 0.002). High-TK1 expression was associated with decreased granzyme B+ CD8+ T cells (ρ=-0.22, P = 0.18), increased PD1+ CD4+ T cells (ρ = 0.33, P = 0.04), increased PDL1+ macrophages (ρ = 0.45, P < 0.001), and increased regulatory T cells (ρ = 0.35, P = 0.03). A novel random forest (RF) risk score was built by machine learning based on TK1 and immunologic parameters. Combined IO + TKI therapy surpassed sunitinib monotherapy in the low RF risk score group (HR = 0.158, P < 0.001), but was inferior to sunitinib in the high RF risk score group (HR, 2.195, P < 0.001).

High-TK1 expression could be a potential indicator for therapeutic resistance, poor PFS and immune evasion in metastatic RCC under IO + TKI therapy. The novel RF risk score may help stratify patients for IO + TKI therapy.

Cancer immunotherapy has attracted great attention as a potential therapeutic approach for advanced malignancies due to its promising survival benefits. Comprehension of intricate interactions between the tumor microenvironment (TME) and immune checkpoint inhibitors (ICIs) is crucial for optimizing and improving immunotherapies. Currently, several experimental strategies are available to monitor this complexity but most of them fail to facilitate real-time monitoring of the immune response such as cellular phagocytosis and cytolysis. Consequently, the application of intravital imaging has been extensively studied in the domain of cancer immunotherapy. Intravital imaging has been proven to be a powerful real-time imaging modality that provides insights into intratumoral immune responses, cellular metabolic signatures, tumor vasculature, and cellular functions. This review aims to provide a comprehensive overview of the latest research on intravital imaging in cancer immunotherapy, especially addressing how intravital imaging sheds light on essential features of tumor immunity, immune infiltrations, tumor angiogenesis, and aids in the clarification of underlying immunotherapeutic mechanisms. Moreover, a variety of labeling tools, imaging windows and models for real-time visualizations of TME are also summarized. We will also investigate the full potential of using intravital imaging to circumvent the limitations of currently available imaging modalities, which hold promise to advent efficient immunotherapy for cancer patients.

Esophageal squamous cell carcinoma (ESCC) is a highly heterogeneous and aggressive malignancy. The progression, invasiveness, and metastatic potential of ESCC are shaped by a multitude of cells within the tumor microenvironment (TME), including tumor cells, immune cells, endothelial cells, as well as fibroblasts and other cell types. Recent advancements in single-cell sequencing technologies have significantly enhanced our comprehension of the diverse landscape of ESCC. Single-cell multi-omics technology, particularly single-cell transcriptome sequencing, have shed light on the expression profiles of individual cells and the molecular characteristics of distinct tumor cell populations. This review summarizes the latest literature on single-cell research in the field of ESCC, aiming to elucidate the heterogeneity of tumor cells, immune cells, and stromal cells at the single-cell level. Furthermore, it explores the impact of cellular interactions within the TME on the progression of ESCC. By compiling a comprehensive overview of single-cell omics research on ESCC, this article aims to enhance our understanding of ESCC diagnosis and treatment by elucidating the intricate interplay within the TME. It explores the cellular composition, spatial arrangement, and functional attributes of the ESCC TME, offering potential therapeutic targets and biomarkers for personalized treatment strategies.

The significance of the controlling nutritional status (CONUT) score in predicting the prognostic outcomes of diffuse large B-cell lymphoma (DLBCL) has been widely explored, with conflicting results. Therefore, the present meta-analysis aimed to identify the prognostic significance of the CONUT in DLBCL by aggregating current evidence.

The Web of Science, PubMed, Embase, CNKI and Cochrane Library databases were searched for articles from inception to October 15, 2024. The prognostic value of CONUT for DLBCL was analyzed by determining the pooled hazard ratios (HRs) with 95% confidence intervals (CIs). The Newcastle-Ottawa Scale (NOS) was used to analyze study quality.

Eight studies including 2687 cases were included in this work. The NOS scores of these studies were 7-9 (median, 8), demonstrating high quality. Our analyses revealed that an elevated CONUT score significantly predicted poor overall survival (OS) (HR = 1.63, 95%CI = 1.29-2.05, p < 0.001) and inferior progression-free survival (PFS) (HR=1.22, 95%CI = 1.12-1.33, p < 0.001) in patients with DLBCL. Further, the elevated CONUT score showed a significant correlation with the following clinicopathological factors in DLBCL: Ann Arbor stage III-IV, Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 2-4, presence of extranodal disease, ≥high intermediate National Comprehensive Cancer Network International Prognostic Index (NCCN IPI), presence of B symptoms, elevated lactose dehydrogenase (LDH) levels, and presence of bone marrow infiltration.

An increased CONUT score was dramatically associated with poor OS and PFS in patients with DLBCL, as well as with clinicopathological characteristics representing DLBCL tumor development.

Endogenous retrovirus (ERV) elements are genomic footprints of ancestral retroviral infections within the human genome. While the dysregulation of ERV transcription has been linked to immune cell infiltration in various cancers, its relationship with immune checkpoint inhibitor (ICI) response in solid tumors, particularly metastatic clear-cell renal cell carcinoma (ccRCC), remains inadequately explored.

This study analyzed patients with metastatic ccRCC from two prospective clinical trials, encompassing 181 patients receiving nivolumab in the CheckMate trials (-009 to -010 and -025) and 48 patients treated with the ipilimumab-nivolumab combination in the BIONIKK trial. ERV expression was quantified using the ERVmap algorithm from RNA sequencing data. Our primary objective was to correlate ERV expression with progression-free survival, with overall survival and time-to-second-treatment survival as secondary endpoints. We used bootstrap methods with univariate Cox regression on 666 substantially expressed ERVs to evaluate their prognostic significance and stability.

Our analysis centered on two ERVs, E4421_chr17 and E1659_chr4, which consistently exhibited opposing prognostic impacts across both cohorts. We developed a stratification system based on their median expression levels, categorizing patients into four ERV subgroups. These subgroups were further consolidated into a three-tier risk model that significantly correlated with ICI treatment outcomes. The most responsive ERV risk category showed enhanced endothelial cell infiltration, whereas the resistant category was characterized by higher levels of myeloid dendritic cells, regulatory T cells, myeloid-derived suppressor cells, and markers of T-cell exhaustion. Notably, this ERV-based classification outperformed traditional transcriptomic signatures in predicting ICI efficacy and showed further improvement when combined with epigenetic DNA methylation markers.

Our findings introduce a dual ERV-based stratification system that effectively categorizes patient risk and predicts clinical outcomes for ccRCC patients undergoing ICI therapy. Beyond enhancing the predictive precision of existing transcriptomic models, this system paves the way for more targeted and individualized approaches in the realm of precision oncology.

We previously developed human CAR macrophages (CAR-M) and demonstrated redirection of macrophage anti-tumor function leading to tumor control in immunodeficient xenograft models. Here, we develop clinically relevant fully immunocompetent syngeneic models to evaluate the potential for CAR-M to remodel the tumor microenvironment (TME), induce T cell anti-tumor immunity, and sensitize solid tumors to PD1/PDL1 checkpoint inhibition. In vivo, anti-HER2 CAR-M significantly reduce tumor burden, prolong survival, remodel the TME, increase intratumoral T cell and natural killer (NK) cell infiltration, and induce antigen spreading. CAR-M therapy protects against antigen-negative relapses in a T cell dependent fashion, confirming long-term anti-tumor immunity. In HER2+ solid tumors with limited sensitivity to anti-PD1 (aPD1) monotherapy, the combination of CAR-M and aPD1 significantly improves tumor growth control, survival, and remodeling of the TME in pre-clinical models. These results demonstrate synergy between CAR-M and T cell checkpoint blockade and provide a strategy to potentially enhance response to aPD1 therapy for patients with non-responsive tumors.

The advancement of high-throughput sequencing technology in recent decades has led to a greater understanding of the components of the oral microbiota, providing a solid foundation for extensive research in this field. The oral microbiota plays an important role in an individual's overall health. It has been shown to be significantly correlated with chronic human diseases, including diabetes, rheumatoid arthritis, cardiovascular disease, periodontal disease, and Alzheimer's disease. Furthermore, tumor occurrence and development are closely related to the oral microbiome. Specific bacteria, such as Fusobacterium nucleatum (F. nucleatum), Porphyromonas gingivalis (P. gingivalis), Streptococcus, Streptomyces, Prevotella, and Fibrophagy gingivalis, play critical roles in cancer development. The oral microbiota has various oncogenic mechanisms, including bacterial inflammation, immunological suppression, tumor growth mediated by bacterial toxins, antiapoptotic activity, and carcinogenic effects. This paper reviews the role of the oral microbiota in the occurrence and progression of cancer and systematically elucidates the molecular mechanisms by which dysbiosis influences tumorigenesis and tumor progression. This information can provide a theoretical basis for exploring cancer treatment strategies and offer new insights for cancer prevention.

Tumor-associated macrophages (TAMs) are one of the key immunosuppressive components in the tumor microenvironment (TME) and contribute to tumor development, progression, and resistance to cancer immunotherapy. Several reagents targeting TAMs have been tested in preclinical and clinical studies, but they have had limited success. Here, we show that a unique reagent, FF-10101, exhibited a sustained inhibitory effect against colony-stimulating factor 1 receptor by forming a covalent bond and reduced immunosuppressive TAMs in the TME, which led to strong antitumor immunity. In preclinical animal models, FF-10101 treatment significantly reduced immunosuppressive TAMs and increased antitumor TAMs in the TME. In addition, tumor antigen-specific CD8+ T cells were increased; consequently, tumor growth was significantly inhibited. Moreover, combination treatment with an anti-programmed cell death 1 (anti-PD-1) antibody and FF-10101 exhibited a far stronger antitumor effect than either treatment alone. In human cancer specimens, FF-10101 treatment reduced programmed cell death 1 ligand 1 (PD-L1) expression on TAMs, as observed in animal models. Thus, FF-10101 acts as an immunomodulatory agent that can reduce immunosuppressive TAMs and augment tumor antigen-specific T cell responses, thereby generating an immunostimulatory TME. We propose that FF-10101 is a potential candidate for successful combination cancer immunotherapy with immune checkpoint inhibitors, such as PD-1/PD-L1 blockade.

Myeloid cells accumulate extensively in most tumors and play a critical role in immunosuppression of the tumor microenvironment (TME). Like T cells, myeloid cells also express immune checkpoint molecules, which induce the immunosuppressive phenotype of these cells. In this review, we summarize the tumor-promoting function and immune checkpoint expression of four types of myeloid cells: macrophages, neutrophils, dendritic cells, and myeloid-derived suppressor cells, which are the main components of the TME. By summarizing the research status of myeloid checkpoints, we propose that blocking immune checkpoints on myeloid cells might be an effective strategy to reverse the immunosuppressive status of the TME. Moreover, combining nanotechnology, cellular therapy, and bispecific antibodies to achieve precise targeting of myeloid immune checkpoints can help to avoid the adverse effects of systemic administration, ultimately achieving a balance between efficacy and safety in cancer therapy.

Dupilumab is the first monoclonal antibody approved for treating moderate-to-severe atopic dermatitis (AD) and has significantly improved the quality of life of AD patients. However, the safety of dupilumab is yet unclear in the context of cancer. Therefore, we aimed to investigate the safety of dupilumab and its relationship with the progression and occurrence of tumors. By reviewing relevant medical records of 90 patients who had pre-existing tumors before dupilumab treatment or presented new tumors after dupilumab treatment, we found that dupilumab probably had no significant negative effects on most tumors, but several patients with Cutaneous T-cell lymphomas (CTCLs) had relatively unfavorable outcomes during dupilumab treatment. Besides, CTCLs and lymphomas accounted for the majority of patients who presented new tumors after dupilumab treatment. Several patients were first diagnosed with presumed AD and probably were the presentations of CTCL at an early stage, and they developed typical CTCL symptoms after dupilumab treatment. Finally we came to the conclusion that dupilumab is safe for most patients with cancer. However, the effect of dupilumab on CTCLs is disputable. The use of dupilumab requires individual evaluation and closely monitored. When the efficacy is poor, re-evaluation of the diagnosis, especially of CTCLs and related diseases, is necessary.

Tumorigenesis embodies the formation of a heterotypic tumour microenvironment (TME) that, among its many functions, enables the evasion of T cell-mediated immune responses. Remarkably, most TME cell types, including cancer cells, fibroblasts, myeloid cells, vascular endothelial cells and pericytes, can be stimulated to deploy immunoregulatory programmes. These programmes involve regulatory inducers (signals-in) and functional effectors (signals-out) that impair CD8+ and CD4+ T cell activity through cytokines, growth factors, immune checkpoints and metabolites. Some signals target specific cell types, whereas others, such as transforming growth factor-β (TGFβ) and prostaglandin E2 (PGE2), exert broad, pleiotropic effects; as signals-in, they trigger immunosuppressive programmes in most TME cell types, and as signals-out, they directly inhibit T cells and also modulate other cells to reinforce immunosuppression. This functional diversity and redundancy pose a challenge for therapeutic targeting of the immune-evasive TME. Fundamentally, the commonality of regulatory programmes aimed at abrogating T cell activity, along with paracrine signalling between cells of the TME, suggests that many normal cell types are hard-wired with latent functions that can be triggered to prevent inappropriate immune attack. This intrinsic capability is evidently co-opted throughout the TME, enabling tumours to evade immune destruction.

PD-1 blockade enhances anti-tumoral CD8+ T cell responses via type 1 conventional dendritic cells (cDC1s), but how cDC1s change the properties of intratumoral CD8+ T cells remains to be determined. Here, we identified two populations of intratumoral CD8+ T cells distinguished by their expression of asialo-ganglio-N-tetraosylceramide (asGM1). asGM1neg and asGM1posCD8+ T cells show enriched expression of genes characteristic for precursor exhausted T (Tpex) cells and terminally exhausted T (Tex) cells, respectively. The in situ expression of Flt3L or inhibition of PD-1 each promote the differentiation of asGM1negCD8+ T cells into asGM1posCD8+ T cells via interleukin-12 (IL-12) while also increasing the expression of Tpex and effector-like T cell-associated genes and their effector functions. Both interventions selectively expand CD8+ T cells, but only Flt3L expression broadens their T cell receptor (TCR) repertoire. These data indicate the distinct role of Flt3L in diversifying the TCR repertoire, offering potential solutions for immune checkpoint blockade-resistant cancers.

The applications of single-cell and spatial technologies in recent times have revolutionized the present understanding of cellular states and the cellular heterogeneity inherent in complex biological systems. These advancements offer unprecedented resolution in the examination of the functional genomics of individual cells and their spatial context within tissues. In this review, we have comprehensively discussed the historical development and recent progress in the field of single-cell and spatial genomics. We have reviewed the breakthroughs in single-cell multi-omics technologies, spatial genomics methods, and the computational strategies employed toward the analyses of single-cell atlas data. Furthermore, we have highlighted the advances made in constructing cellular atlases and their clinical applications, particularly in the context of disease. Finally, we have discussed the emerging trends, challenges, and opportunities in this rapidly evolving field.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by the absence of progesterone and estrogen receptors and low (or absent) HER2 expression. TNBC accounts for 15-20% of all breast cancers. It is associated with younger age, a higher mutational burden, and an increased risk of recurrence and mortality. Standard treatment for TNBC primarily relies on cytotoxic agents, such as taxanes, anthracyclines, and platinum compounds for both early and advanced stages of the disease. Several targeted therapies, including bevacizumab and sunitinib, have failed to demonstrate significant clinical benefit in TNBC. The emergence of immune checkpoint inhibitors (ICI) has revolutionized cancer treatment. By stimulating the immune system, ICIs induce a durable anti-tumor response across various solid tumors. TNBC is a particularly promising target for treatment with ICIs due to the higher levels of tumor-infiltrating lymphocytes (TIL), increased PD-L1 expression, and higher mutational burden, which generates tumor-specific neoantigens that activate immune cells. ICIs administered as monotherapy in advanced TNBC yields only a modest response; however, response rates significantly improve when ICIs are combined with cytotoxic agents, particularly in tumors expressing PD-L1. Pembrolizumab is approved for use in both early and advanced TNBC in combination with standard chemotherapy. However, more research is needed to identify more potent biomarkers, and to better elucidate the synergism of ICIs with other targeted agents. In this review, we explore the challenges of immunotherapy in TNBC, examining the mechanisms of tumor progression mediated by immune cells within the tumor microenvironment, and the signaling pathways involved in both primary and acquired resistance. Finally, we provide a comprehensive overview of ongoing clinical trials underway to investigate novel immune-targeted therapies for TNBC.

Cardiovascular diseases and cancer represent the largest disease burden worldwide. Previously, these two conditions were considered independent, except in terms of cardiotoxicity, which links cancer treatment to subsequent cardiovascular issues. However, recent studies suggest that there are further connections between cancer and heart disease beyond cardiotoxicity. It has been revealed that myocardial dysfunction may promote carcinogenesis, indicating that additional common pathophysiological mechanisms might be involved in the relationship between cardiology and oncology, rather than simply a connection through cardiotoxic effects. These mechanisms may include shared risk factors and common molecular pathways, such as persistent inflammation and neurohormonal activation. This review explores the connection between myocardial dysfunction and cancer, emphasizing their shared risk factors, similar biological mechanisms, and causative factors like cardiotoxicity, along with their clinical implications.

The potential of preoperative CT in the assessment of myeloid immune response and its application in predicting prognosis and immune-checkpoint therapy outcomes in hepatocellular carcinoma (HCC) has not been explored.

A total of 165 patients with pathological slides and multi-phase CT images were included to develop a radiomics signature for predicting the imaging-based myeloid response score (iMRS). Overall survival (OS) and recurrence-free survival (RFS) were assessed according to the iMRS risk group and validated in a surgical resection cohort (n = 98). The complementary advantage of iMRS incorporating significant clinicopathologic factors was investigated by the Cox proportional hazards analysis. Additionally, the iMRS in inferring the benefits of immune checkpoint therapy was explored in an immunotherapy cohort (n = 36).

We showed that AUCs of the optimal radiomics signature for iMRS were 0.941 [95% confidence interval (CI), 0.909-0.973] and 0.833 (0.798-0.868) in the training and test cohorts, respectively. High iMRS was associated with poor RFS and OS. The prognostic performance of the Clinical-iMRS nomogram was better than that of a single parameter (p < 0.05), with a 1-, 3-, and 5-year C-index for RFS of 0.729, 0.709, and 0.713 in the training, test, and surgical resection cohorts, respectively. A high iMRS score predicted a higher proportion of objective response (vs. progressive disease or stable disease; odds ratio, 2.311; 95% CI, 1.144-4.672; p = 0.020; AUC, 0.718) in patients treated with anti-PD-1 and PD-L1.

iMRS may provide a promising method for predicting local myeloid immune responses in HCC patients, inferring postsurgical prognosis, and evaluating benefits of immune checkpoint therapy.

Brain diseases are a significant threat to human health, especially in the elderly, and this problem is growing as the aging population increases. Efficient brain-targeted drug delivery has been the greatest challenge in treating brain disorders due to the unique immune environment of the brain, including the blood-brain barrier (BBB). Recently, cerebral biomimetic nano-drug delivery systems (CBNDSs) have provided a promising strategy for brain targeting by mimicking natural biological materials. Herein, this review explores the latest understanding of the immune microenvironment of the brain, emphasizing the immune mechanisms of the occurrence and progression of brain disease. Several brain targeting systems are summarized, including cell-based, exosome-based, protein-based, and microbe-based CBNDSs, and their immunological mechanisms are highlighted. Moreover, given the rise of immunotherapy, the latest applications of CBNDSs in immunotherapy are also discussed. This review provides a comprehensive understanding of CBNDSs and serves as a guideline for immunotherapy in treating brain diseases. In addition, it provides inspiration for the future of CBNDSs.

Numerous human cancers have exhibited the ability to elude immune checkpoint blockade (ICB) therapies. This type of resistance can be mediated by immune-suppressive macrophages that limit antitumor immunity in the tumor microenvironment (TME). Here, we elucidate a strategy to shift macrophages into a proinflammatory state that down-regulates V domain immunoglobulin suppressor of T cell activation (VISTA) via inhibiting AhR and IRAK1. We used a high-throughput microfluidic platform combined with a genome-wide CRISPR knockout screen to identify regulators of VISTA levels. Functional characterization showed that the knockdown of these hits diminished VISTA surface levels on macrophages and sustained an antitumor phenotype. Furthermore, targeting of both AhR and IRAK1 in mouse models overcame resistance to ICB treatment. Tumor immunophenotyping indicated that infiltration of cytotoxic CD8+ cells, natural killer cells, and antitumor macrophages was substantially increased in treated mice. Collectively, AhR and IRAK1 are implicated as regulators of VISTA that coordinate a multifaceted barrier to antitumor immune responses.

Breast cancer remains one of the leading causes of death in women around the world. A majority of deaths from breast cancer occur due to cancer cells colonizing distant organ sites. When colonizing these distant organ sites, breast cancer cells have been known to enter into a state of dormancy for extended periods of time. However, the mechanisms that promote dormancy as well as dormant-to-proliferative switch are not fully understood. The tumor microenvironment plays a key role in mediating cancer cell phenotype including regulation of the dormant state. In this review, we highlight cell-cell interactions in the tumor microenvironment mediating breast cancer dormancy at the primary and metastatic sites. Specifically, we describe how immune cells from the lymphoid lineage, tumor-associated myeloid lineage cells, and stromal cells of non-hematopoietic origin as well as tissue resident stromal cells impact dormancy vs. proliferation in breast cancer cells as well as the associated mechanisms. In addition, we highlight the importance of developing model systems and the associated considerations that will be critical in unraveling the mechanisms that promote primary and metastatic breast cancer dormancy mediated via cell-cell interactions.

The liver is the predominant metastatic site for diverse cancers, including pancreatic and colorectal cancers (CRC), etc. The high incidence of hepatic metastasis of pancreatic cancer is an important reason for its refractory and high mortality. Therefore, it is important to understand how metastatic pancreatic cancer affects the hepatic tumor immune microenvironment (TME) in patients. Here, we characterized the TME of liver metastases unique to pancreatic cancer by comparing them with CRC liver metastases. We integrated two single-cell RNA-seq (scRNA-seq) datasets including tumor samples of pancreatic cancer liver metastasis (P-LM), colorectal cancer liver metastasis (C-LM), primary pancreatic cancer (PP), primary colorectal cancer (PC), as well as samples of peripheral blood mono-nuclear cells (PBMC), adjacent normal pancreatic tissues (NPT), to better characterize the heterogeneities of the microenvironment of two kinds of liver metastases. We next performed comparative analysis on cellular compositions between P-LM and C-LM, found that Mph_SPP1, a subset of macrophages associated with angiogenesis and tumor invasion, was more enriched in the P-LM group, indicating this kind of macrophages provide a TME niche more vulnerable for pancreatic cancers. Analysis of the developmental trajectory implied that Mph_SPP1 may progressively be furnished with increased expression of genes regulating endothelium. Cell-cell communications analysis revealed that Mph_SPP1 potentially interacts with endothelial cells in P-LM via FN1/SPP1-ITGAV/ITGB1, implying this macrophage subset may construct an immunosuppressive TME for pancreatic cancer by regulating endothelial cells. We also found that Mph_SPP1 has a prognostic value in pancreatic adenocarcinoma that is not present in colon adenocarcinoma or rectum adenocarcinoma. This study provides a new perspective for understanding the characteristics of the hepatic TME in patients with liver metastatic cancer. And it provides a subset of macrophages specifically associated with the liver metastasis of pancreatic cancer, and its detection and intervention have potential value for preventing the metastasis of pancreatic cancer to the liver.

Cancer and cardiovascular disease (CVD) are leading causes of mortality and thus represent major health challenges worldwide. Clinical data suggest that cancer patients have an increased likelihood of developing cardiovascular disease, while epidemiologic studies have shown that patients with cardiovascular disease are also more likely to develop cancer. These observations underscore the increasing importance of studies exploring the mechanisms underlying the interaction between the two diseases. We review their common physiological processes and potential pathophysiological links. We explore the effects of chronic inflammation, oxidative stress, and disorders of fatty acid metabolism in CVD and cancer, and also provide insights into how cancer and its treatments affect heart health, as well as present recent advances in reverse cardio-oncology using a new classification approach.

In continuously progressive tumor tissues, the causes of cellular stress are multiple: metabolic alterations, nutrient deprivation, chronic inflammation and hypoxia. To survive, tumor cells activate the stress response program, a highly conserved molecular reprogramming proposed to cope with challenges in a hostile environment. Not only cancer cells are affected, but stress responses in tumors also have a profound impact on their normal cellular counterparts: fibroblasts, endothelial cells and infiltrating immune cells. In recent years, there has been a growing interest in the interaction between cancer and immune cells, especially in difficult conditions of cellular stress. A growing literature indicates that knowledge of the molecular pathways activated in tumor and immune cells under stress conditions may offer new insights for possible therapeutic interventions. Counter-regulating the stress caused by the presence of a growing tumor can therefore be a weapon to limit disease progression. Here, we review the main pathways activated in cellular stress responses with a focus on immune cells present in the tumor microenvironment.

Background: Resistance to standard therapeutic methods, including chemotherapy, immunotherapy, and targeted therapy, remains a critical challenge in effective cancer treatment. Redox homeostasis modification has emerged as a promising approach to address medication resistance. Objective: This review aims to explore the mechanisms of redox alterations and signaling pathways contributing to treatment resistance in cancer. Methods: In this study, a comprehensive review of the molecular mechanisms underlying drug resistance governed by redox signaling was conducted. Emphasis was placed on understanding how tumor cells manage increased reactive oxygen species (ROS) levels through upregulated antioxidant systems, enabling resistance across multiple therapeutic pathways. Results: Key mechanisms identified include alterations in drug efflux, target modifications, metabolic changes, enhanced DNA damage repair, stemness preservation, and tumor microenvironment remodeling. These pathways collectively facilitate tumor cells' adaptive response and resistance to various cancer treatments. Conclusion: Developing a detailed understanding of the interrelationships between these redox-regulated mechanisms and therapeutic resistance holds potential to improve treatment effectiveness, offering valuable insights for both fundamental and clinical cancer research. Antioxid. Redox Signal. 00, 000-000.

The efficacy of immune checkpoint inhibitors in the treatment of hepatocellular carcinoma (HCC) remains limited, highlighting the need for further investigation into the mechanisms underlying treatment resistance. Accumulating evidence indicates that tumor-associated macrophages (TAM) within the tumor microenvironment demonstrate a key role in immune evasion and treatment resistance. This study explored the role of TAMs in the HCC tumor microenvironment. Our findings reveal that TAMs expressing CX3C motif chemokine receptor 1 (CX3CR1) induced T-cell exhaustion through IL27 secretion in orthotopic models of HCC following treatment with anti-PD1. Moreover, we identified prostaglandin E2 (PGE2), released by immune-attacked tumor cells, as a key regulator of TAM transition to a CX3CR1+ phenotype. To augment the therapeutic response to anti-PD1 therapy, we propose targeting CX3CR1+ TAMs in addition to anti-PD1 therapy. Our study contributes to the understanding of the role of TAMs in cancer immunotherapy and highlights potential clinical implications for HCC treatment. The combination of targeting CX3CR1+ TAMs with anti-PD1 therapy holds promise for enhancing the efficacy of immunotherapeutic interventions in patients with HCC.

Macrophages are essential in maintaining homeostasis, combating infections, and influencing the process of various diseases, including cancer. Macrophages originate from diverse lineages: Notably, tissue-resident macrophages (TRMs) differ from hematopoietic stem cells and circulating monocyte-derived macrophages based on genetics, development, and function. Therefore, understanding the recruited and TRM populations is crucial for investigating disease processes.

By searching literature databses, we summarized recent relevant studies. Research has shown that tumor-associated macrophages (TAMs) of distinct origins accumulate in tumor microenvironment (TME), with TRM-derived TAMs closely resembling gene signatures of normal TRMs.

Recent studies have revealed that TRMs play a crucial role in cancer progression. However, organ-specific effects complicate TRM investigations. Nonetheless, the precise involvement of TRMs in tumors is unclear. This review explores the multifaceted roles of TRMs in cancer, presenting insights into their origins, proliferation, the latest research methodologies, their impact across various tumor sites, their potential and strategies as therapeutic targets, interactions with other cells within the TME, and the internal heterogeneity of TRMs.

We believe that a comprehensive understanding of the multifaceted roles of TRMs will pave the way for targeted TRM therapies in the treatment of cancer.

Overcoming resistance to immunotherapy in cancer is challenging due, in part, to tumor-associated macrophages (TAMs) co-expressing T cell immunoglobulin and mucin domain-containing 3 (TIM3) and V-domain immunoglobulin suppressor of T cell activation (VISTA) in tumor microenvironments (TME) with sparse T cell infiltration. In a recent article, Vanmeerbeek et al. found that blocking TIM3 or VISTA on IL-4-supported TAMs, in combination with paclitaxel (PTX), reprogrammed TAMs to attack cancer cells, highlighting a potential new therapeutic strategy.

Regulating innate immunity is an emerging approach to improve cancer immunotherapy. Such regulation requires engaging myeloid cells by delivering immunomodulatory compounds to hematopoietic organs, including the spleen. Here we present a polymersome-based nanocarrier with splenic avidity and propensity for red pulp myeloid cell uptake. We characterized the in vivo behaviour of four chemically identical yet topologically different polymersomes by in vivo positron emission tomography imaging and innovative flow and mass cytometry techniques. Upon intravenous administration, relatively large and spherical polymersomes accumulated rapidly in the spleen and efficiently targeted myeloid cells in the splenic red pulp. When loaded with β-glucan, intravenously administered polymersomes significantly reduced tumour growth in a mouse melanoma model. We initiated our nanotherapeutic's clinical translation with a biodistribution study in non-human primates, which revealed that the platform's splenic avidity is preserved across species.