Ischemia-reperfusion injury (IRI) is closely associated with numerous severe postoperative complications, including acute rejection, delayed graft function (DGF) and graft failure. Macrophages are central to modulating the aseptic inflammatory response during the IRI process. The objective of this study is to conduct an analysis of the developmental and differentiation characteristics of macrophages in IRI, identify distinct molecules subtypes of IRI, and establish robust predictive strategies for DGF and graft survival.

We analyzed scRNA-Seq data from GEO database to identify macrophage sub-clusters specific to renal IRI, and use the hdWGCNA algorithm to screen gene modules closely associated with this sub-cluster. Integrating these module genes with the results from bulk RNA-Seq differential analysis to obtain hub genes, and delineating the different IRI molecular subtypes through consensus clustering based on the expression profiles of hub genes. Innovatively, the gene expression matrix was transformed into a unique graphic pixel module and applied advanced computer vision processing algorithms to construct a DGF predictive model. Additionally, we also employed 111 combinations of 10 machine learning algorithms to develop a predictive signature for graft survival. Finally, we validated the expression of the key gene ANXA1 in a mouse IRI model using qRT-PCR, WB, and IHC.

This study successfully identified a subset of macrophages closely associated with renal IRI, and cell communication and pseudo-time analysis implied that they may be instrumental in both the maintenance and exacerbation of the IRI process. Utilizing the expression patterns of hub genes, recipients can be clustered into two subtypes (CI and C2) with unique clinical and molecular features. We innovatively applied deep learning algorithms to construct a model for DGF prediction, which can effectively mitigate batch effects among IRI recipients. Compared to other existing models, our model demonstrated superior performance with AUC of 0.816 and 0.845 in the training and validation set. Furthermore, we also used the random survival forest algorithm to develop a high-precision predictive signature for graft failure. The mouse IRI model confirmed a marked upregulation of ANXA1 mRNA and protein expression in renal tissue following IRI.

This study successfully revealed the macrophage sub-cluster closely associated with renal IRI. Two distinct IRI subgroups with different characteristics were identified and robust strategies were constructed for predicting DGF and graft survival, which can offer potential therapeutic targets for the treatment of IRI and reference for early prevention of various postoperative complications.

Cancer stem cells (CSCs) depend on the tumor microenvironment (TME) to sustain their stem-like properties by recruiting monocytes and reprogramming them into tumor-associated macrophages (TAMs), which in turn promote tumor progression. This review explores CSC-TAM interactions, emphasizing how CSCs drive monocyte recruitment and TAM polarization. We discuss how TAMs enhance CSC stemness and niche maintenance through chemokines, cytokines, exosome-mediated miRNA transfer, direct interactions, and extracellular matrix (ECM) remodeling. Furthermore, we examine therapeutic strategies targeting TAMs, including inhibiting TAM differentiation, reprogramming TAM polarization, and leveraging immune checkpoint blockade and CAR-macrophage immunotherapy to improve cancer treatment outcomes.

Esophageal squamous cell carcinoma (ESCC) stands out as a common cancer type worldwide, characterized by its notably high rates of occurrence and mortality. The epidermal growth factor receptor (EGFR) is one of the main targets for cancer treatment as it is one of the genes whose expression is often altered by overexpression, amplification, and mutation in a variety of solid tumors. Substantial efforts have been made to develop EGFR-targeted therapeutic agents, including monoclonal antibodies and tyrosine kinase inhibitors (TKIs). However, these agents exhibited limited efficacy due to the emergence of acquired resistance. Therefore, novel treatment strategies targeting EGFR are urgently needed. Recent studies have identified a few natural compounds that can efficiently inhibit EGFR, indicating that natural products may be potential sources for the development of new EGFR inhibitors. Here, using the Drug Affinity Responsive Target Stability (DARTS) assay combined with liquid chromatography/tandem mass spectrometry analysis, co-crystal method, we discovered that Bufalin directly interacts with EGFR and causes EGFR endocytosis and degradation in the lysosome. Moreover, Bufalin exhibits superior anti-tumor activity compared with another EGFR TKIs. Our study identified Bufalin as the first natural small-molecule EGFR degrader, which suppresses EGFR signaling by inducing the degradation of EGFR via the endosome-lysosome pathway.

Tumor microenvironment (TME) refers to the local environment in which various cancer cells grow, encompassing tumor cells, adjacent non-tumor cells, and associated non-cellular elements, all of which collectively promote cancer occurrence and progression. As a principal immune component in the TME, tumor-associated macrophages (TAMs) exert a considerable influence on cancer behaviors via their interactions with cancer cells. The interactive loops between cancer cells and TAMs, including secretory factors derived from both cancer cells and TAMs, are crucial for the proliferation, stemness, drug resistance, invasion, migration, metastasis, and immune escape of various cancers. Cancer cells release paracrine proteins (HMGB1, AREG etc.), cytokines (IL-6, CCL2 etc.), RNAs (miR-21-5p, circPLEKHM1, LINC01812 etc.), and metabolites (lactic acid, succinate etc.) to regulate the polarization phenotype, mediator secretion and function of TAMs. In turn, mediators (TGF-β, IL-10, IL-6 etc.) from TAMs promote cancer progression. This review summarizes recent advancements in the interactive loops between cancer cells and TAMs in TME. Inhibiting the recruitment and M2 polarization of TAMs, reprogramming TAMs from M2 to M1 phenotype, blocking TAMs-mediated immunosuppression and immune escape, and combining with existing immunotherapy can target TAMs to overcome immunotherapy resistance in various cancers. The new breakthroughs lie in identifying effective targets for drug development, improving the drug delivery system to enhance the drug delivery efficiency, and adopting combined therapy. Interventions targeting secretory factors, cell surface receptors, intracellular signaling pathways, and metabolic modulation in the interactive loops between cancer cells and TAMs are expected to suppress cancer progression and improve therapeutic effects.

Proteomics studies have advanced our comprehension of cancer biology, accelerated targeted therapy, and improved patient outcomes.

High-resolution mass spectrometry and immune profiling based on immunohistochemistry and multiple immunohistochemistry were employed to investigate proteomic and immune landscapes in oesophageal squamous cell carcinoma (ESCC) and explore the regulators of PD-L1 in ESCC. Molecular validation was performed using qRT-PCR, western blotting, and in vitro functional assays.

Proteomic profiling of 89 treatment-naive ESCC specimens identified over 9300 proteins, with 6900 proteins detected across most samples. Proteome-based stratification identified three subtypes related to diverse clinical and molecular features. Combined proteomics and immune analyses revealed core proteins associated with the immune landscape in ESCC. Further, integrated proteomics, transcriptomics, and immune profiling nominated COTL1 as a potential regulator of PD-L1 in ESCC. Overexpression of COTL1 upregulated both mRNA and protein levels of PD-L1 and promoted cell proliferation in ESCC. Patients with high COTL1 protein expression were likely to have a poor prognosis, along with increased infiltration of CD4+CD8+ and CD4+GrB+ cells.

Collectively, our integrative analysis enables a more comprehensive understanding of the proteomic and immune landscape of ESCC and implicates COTL1 as a potential modulator of PD-L1 and immune cell infiltration.

The optimal timing of pembrolizumab with chemoradiation (CRT) in locally advanced (LA) head and neck squamous cell carcinoma (HNSCC) is unknown.

Our phase II trial randomly assigned patients 1:1 to concurrent pembrolizumab (200 mg once every 3 weeks × 8) starting 1 week before CRT (cisplatin 40 mg/m2 once weekly + radiation 70 Gy) versus sequential pembrolizumab starting 2 weeks after CRT. Human papillomavirus (HPV)+ (>10 pack-years or T4 or N3) and HPV(-) LA HNSCC were included, stratified by HPV and N stage. In our pick-the-winner design, if both arms met the trivariate primary end point (1-year locoregional failure <60%, progression-free survival [PFS] ≥60%, and dose limiting toxicity rate ≤20%), the arm with numerically superior 1-year PFS would be selected. Survival end points were compared by a univariate Cox model. Pretreatment and on-treatment tumor biopsies (week 2 of CRT) were evaluated by multispectral imaging and compared using two-sided paired t-tests.

Treated patients (41 concurrent and 39 sequential) were 71% oropharynx (53% HPV+), 92.5% stage IV (46% T4, 76% N2), similar by arm. Both arms met the trivariate primary end point, with superior 1-year PFS in the sequential arm (84% v 71%) and favorable 4-year outcomes: locoregional control (96% v 64%; hazard ratio [HR], 0.11 [95% CI, 0.01 to 0.89]; P = .012), PFS (69% v 49%; HR, 0.55 [95% CI, 0.25 to 1.22]; P = .132), and overall survival (83% v 71%; HR, 0.51 [95% CI, 0.19 to 1.37]; P = .17). There was a significant increase in macrophages, PD-L1+ macrophages, and PD-L1+ tumor cells with treatment in the concurrent but not the sequential arm.

CRT with sequential pembrolizumab met criteria for further study. Immunosuppressive changes in the TME differed between arms, reflecting the impact of one dose of pembrolizumab in the concurrent arm.

Tumor-associated macrophages' (TAMs) origin, polarization, and dynamic interaction in the tumor microenvironment (TME) influence cancer development. They are essential for homeostasis, monitoring, and immune protection. Cells from bone marrow or embryonic progenitors dynamically polarize into pro- or anti-tumor M2 or M1 phenotypes based on cytokines and metabolic signals. Recent advances in TAM heterogeneity, polarization, characterization, immunological responses, and therapy are described here. The manuscript details TAM functions and their role in resistance to PD-1/PD-L1 blockade. Similarly, TAM-targeted approaches, such as CSF-1R inhibition or PI3Kγ-driven reprogramming, are discussed to address anti-tumor immunity suppression. Furthermore, innovative biomarkers and combination therapy may enhance TAM-centric cancer therapies. It also stresses the relevance of this distinct immune cell in human health and disease, which could impact future research and therapies.

Despite the significant advances in the development of immune checkpoint inhibitors (ICI), primary and acquired ICI resistance remains the primary impediment to effective cancer immunotherapy. Residing in the tumor microenvironment (TME), tumor-associated macrophages (TAMs) play a pivotal role in tumor progression by regulating diverse signaling pathways. Notably, accumulating evidence has confirmed that TAMs interplay with various cellular components within the TME directly or indirectly to maintain the dynamic balance of the M1/M2 ratio and shape an immunosuppressive TME, consequently conferring immune evasion and immunotherapy tolerance. Detailed investigation of the communication network around TAMs could provide potential molecular targets and optimize ICI therapies. In this review, we systematically summarize the latest advances in understanding the origin and functional plasticity of TAMs, with a focus on the key signaling pathways driving macrophage polarization and the diverse stimuli that regulate this dynamic process. Moreover, we elaborate on the intricate interplay between TAMs and other cellular constituents within the TME, that is driving tumor initiation, progression and immune evasion, exploring novel targets for cancer immunotherapy. We further discuss current challenges and future research directions, emphasizing the need to decode TAM-TME interactions and translate preclinical findings into clinical breakthroughs. In conclusion, while TAM-targeted therapies hold significant promise for enhancing immunotherapy outcomes, addressing key challenges-such as TAM heterogeneity, context-dependent plasticity, and therapeutic resistance-remains critical to achieving optimal clinical efficacy.

The comparative efficacy and safety of programmed death-ligand 1 (PD-L1) inhibitors versus programmed death protein 1 (PD-1) inhibitors in breast cancer treatment remain inconclusive, as no head-to-head randomized controlled trials (RCTs) conducted. This study aims to evaluate the efficacy and safety of PD-1/PD-L1 inhibitors as monotherapy or in combination with chemotherapy for breast cancer. A systematic review and meta-analysis were performed using major databases and oncology conference proceedings. The primary outcomes were overall survival (OS) for advanced breast cancer and pathological complete response (PCR) rate for early breast cancer. Secondary outcomes included progression-free survival (PFS) for advanced breast cancer and incidence of adverse events (AEs). Seventeen studies met the inclusion criteria, consisting of seven RCTs on early-stage and 10 on advanced breast cancer. For advanced breast cancer, PD-1/PD-L1 inhibitors modestly improved OS compared to chemotherapy, with no significant differences between PD-1 and PD-L1 inhibitors. PD-L1 inhibitors showed greater improvement in PFS compared to PD-1 inhibitors. The likelihood of AEs of any grade was higher with PD-L1 inhibitor treatment than with PD-1 inhibitor treatment. In early breast cancer, combining PD-1/PD-L1 inhibitors with chemotherapy inducing higher PCR rates than chemotherapy alone, with PD-1 inhibitors achieving better outcomes than PD-L1 inhibitors. PD-1 inhibitors were linked to slightly higher rates of grade >2 AEs compared to PD-L1 inhibitors. The findings indicate that PD-1 inhibitors may offer advantages for advanced breast cancer due to similar OS and a lower rate of AEs. For early breast cancer, PD-1 inhibitors are recommended given their superior PCR rates.

Pulmonary hypertension (PH) is a lethal disease characterized in part by progressive pulmonary arteriole (PA) remodeling. Excessive PA fibrosis and macrophage infiltration are often present in PH, but the potential associations are obscure. We investigated the link between interstitial macrophage (iMΦ) infiltration and PA fibrosis in PH and idiopathic pulmonary arterial hypertension.

Lung tissue samples from patients with idiopathic pulmonary arterial hypertension and experimental PH animals were obtained to analyze the extent of fibrosis and iMΦ infiltration in the different layers of PAs and their correlation with disease severity. Single-cell RNA sequencing, lineage tracing, histological analyses, iMΦ and PA smooth muscle cell coculture, and transgenic animal experiments were used to investigate the cell heterogeneity and origins and molecular mechanisms by which iMΦs promote PA fibrosis.

We found that increased collagen deposition and fibrosis in the PA media were most strongly related to the severity of PH, and medial iMΦ infiltration may be involved in these pathological processes. Single-cell transcriptomics revealed that MHCIIhiLYVE1loCCR2hi iMΦs were the major type of iMΦ that expanded upon Sugen-5416 and hypoxia plus normoxia stimulation and were responsible for PA medial fibrosis. Lineage tracing experiments suggested that these medial iMΦs were largely from recruited monocytes. Mechanistically, MHCIIhiLYVE1loCCR2hi iMΦs promoted the transition of PA smooth muscle cells to a fibroblast-like phenotype through the WNT11 (wingless member 11)/planar cell polarity (PCP) pathway. Wnt11 deletion in iMΦs from PH rats normalized the fibrotic PA smooth muscle cell phenotype and decreased PA medial fibrosis, thereby improving vascular compliance and protecting against PH. Moreover, myeloid-specific Ccr2 deficiency in PH-PAs inhibited the medial infiltration of MHCIIhiLYVE1loCCR2hi iMΦs, which also relieved PH.

This study demonstrates that the recruitment of MHCIIhiLYVE1loCCR2hi iMΦs leads to medial fibrosis in PH-PAs associated with PH severity and that inhibition of their pathogenicity or recruitment reverses PA medial fibrosis and PH.

C-C motif ligand 11 (CCL11) is a multifunctional chemokine that regulates immunity, angiogenesis, and tissue remodeling. In addition to its allergic inflammation role, CCL11 exhibits context-dependent dual functions in relation to cancer progression. In liver diseases, it mediates injury, fibrosis, and inflammation while serving as a disease biomarker. This review systematically examines CCL11-receptor interactions and their immunomodulatory mechanisms in cancers and hepatic pathologies. We highlight CCL11's therapeutic potential as both a prognostic marker and immunotherapeutic target. By integrating molecular and clinical insights, this work advances the understanding of CCL11's pathophysiological roles and facilitates targeted therapy development.

Osteosarcoma (OS) is the most common malignant tumor of bone in children and adolescents. Although lung metastasis is a major obstacle to improving the prognosis of OS patients, the underlying mechanism of lung metastasis of OS is poorly understood. Tumor-associated macrophages (TAMs) with M2-like characteristics are reportedly associated with lung metastasis and poor prognosis in OS patients. In this study, we investigated the metastasis-associated tumor microenvironment (TME) in orthotopic OS tumor models with non-metastatic and metastatic OS cells. Non-metastatic and metastatic tumor cells derived from mouse OS (Dunn and LM8) and human OS (HOS and 143B) were used to analyze the TME associated with lung metastasis in orthotopic OS tumor models. OS cell-derived secretion factors were identified by cytokine array and enzyme-linked immunosorbent assay (ELISA). Orthotopic tumor models with metastatic LM8 and 143B cells were analyzed to evaluate the therapeutic potential of a neutralizing antibody in the development of primary and metastatic tumors. Metastatic OS cells developed metastatic tumors with infiltration of M2-like TAMs in the lungs. Cytokine array and ELISA demonstrated that metastatic mouse and human OS cells commonly secreted CCL2, which was partially encapsulated in extracellular vesicles. In vivo experiments demonstrated that while primary tumor growth was unaffected, administration of CCL2-neutralizing antibody led to a significant suppression of lung metastasis and infiltration of M2-like TAMs in the lung tissue. Our results suggest that CCL2 plays a crucial role in promoting the lung metastasis of OS cells via accumulation of M2-like TAMs.

Immunotherapy is increasingly integral to breast cancer treatment, yet a subset develops resistance, partly mediated by macrophages and monocytes in the tumor immune microenvironment. While macrophages play essential roles in phagocytosis and pathogen clearance, their dual role in breast cancer-acting as both barriers to therapy and potential therapeutic targets-complicates treatment efficacy.

Tumor-associated macrophages, polarized by tumor-derived signals, promote cancer progression and metastasis. Monocytes, subdivided into CD14+CD16- and CD14+CD16+ subsets, exhibit distinct functional profiles in cytokine secretion, antigen presentation, and migration. Modulating monocyte subset dynamics and functionality may enhance immunotherapy responsiveness.

A multimodal strategy targeting macrophages, monocytes, and complementary immunotherapies offers promising avenues to overcome resistance. Further research into the heterogeneity and regulatory mechanisms of these cells is critical for developing optimized, safe immunotherapeutic protocols. This review underscores the necessity of combination immunotherapies to improve outcomes in breast cancer.

Tumor-associated macrophages (TAMs) contribute to tumor progression by promoting angiogenesis, remodeling the tumor extracellular matrix, inducing tumor invasion and metastasis, as well as immune evasion. Due to the high plasticity of TAMs, they can polarize into different phenotypes with distinct functions, which are primarily categorized as the pro-inflammatory, anti-tumor M1 type, and the anti-inflammatory, pro-tumor M2 type. Notably, anti-tumor macrophages not only directly phagocytize tumor cells, but also present tumor-specific antigens and activate adaptive immunity. Therefore, targeted regulation of TAMs to unleash their potential anti-tumor capabilities is crucial for improving the efficacy of cancer immunotherapy. Nanomedicine serves as a promising vehicle and can inherently interact with TAMs, hence, emerging as a new paradigm in cancer immunotherapy. Due to their controllable structures and properties, nanomedicines offer a plethora of advantages over conventional drugs, thus enhancing the balance between efficacy and toxicity. In this review, we provide an overview of the hallmarks of TAMs and discuss nanomedicines for targeting TAMs with a focus on inhibiting recruitment, depleting and reprogramming TAMs, enhancing phagocytosis, engineering macrophages, as well as targeting TAMs for tumor imaging. We also discuss the challenges and clinical potentials of nanomedicines for targeting TAMs, aiming to advance the exploitation of nanomedicine for cancer immunotherapy.

Tumor metabolism plays a pivotal role in shaping immune responses within the tumor microenvironment influencing tumor progression, immune evasion, and the efficacy of cancer therapies. Radiotherapy has been shown to impact both tumor metabolism and immune modulation, often inducing immune activation through damage-associated molecular patterns and the STING pathway. In this study, we analyse the particular characteristics of the tumour metabolic microenvironment and its effect on the immune microenvironment. We also review the changes in the metabolic and immune microenvironment that are induced by radiotherapy, with a focus on metabolic sensitisation to the effects of radiotherapy. Our aim is to contribute to the development of research ideas in the field of radiotherapy metabolic-immunological studies.

Oral cancer remains a significant public health concern, with many patients diagnosed at advanced stages and facing poor prognoses. Despite advances in cancer research, diagnosis has seen only limited improvements, with biopsies still being the primary reliable method. This systematic review investigates the role of chemokines as potential biomarkers for early detection, prognosis, and metastasis in oral squamous cell carcinoma (OSCC) and oral potentially malignant disorders (OPMDs). Through an extensive literature search of MEDLINE, EMBASE, PubMed, and Scopus, 3350 articles were initially identified. After eliminating duplicates and screening for eligibility, 50 high-quality studies were included, offering a comprehensive overview of chemokine research in OSCC and OPMDs. Key findings indicate that CCR7 shows significant promise as a diagnostic, prognostic, and metastatic marker, although its function in precancerous conditions remains inadequately understood. CXCL10 and CCL22 were also highlighted for their strong prognostic and metastatic relevance, while CXCR4 and CXCL12 were identified as critical indicators of OSCC metastasis. Other chemokines, such as CXCR2, CCR4, XCR1, CXCL13, and CCL2 can aid OSCC differentiation and staging. However, the review emphasises the limitations of small patient cohorts and the lack of longitudinal research, stressing the need for further studies. Additionally, there is a pressing gap in research addressing chemokines as biomarkers for OPMDs. Rigorous validation is crucial to establish these biomarkers' reliability and clinical utility across various stages of oral cancer development.

Neoantigen vaccines are among the most potent immunotherapies for personalized cancer treatment. Therapeutic vaccines containing tumor-specific neoantigens that elicit specific T cell responses offer the potential for long-term clinical benefits to cancer patients. Unlike immune-checkpoint inhibitors (ICIs), which rely on pre-existing specific T cell responses, personalized neoantigen vaccines not only promote existing specific T cell responses but importantly stimulate the generation of neoantigen-specific T cells, leading to the establishment of a persistent specific memory T cell pool. The review discusses the current state of clinical research on neoantigen nanovaccines, focusing on the application of vectors, adjuvants, and combinational strategies to address a range of challenges and optimize therapeutic outcomes.

Tumor-associated macrophages (TAMs) primarily exist in the M2-like phenotype in the tumor microenvironment (TME). M2-TAMs contribute to tumor progression by establishing an immunosuppressive environment. However, TAM targeting is hindered, mainly owing to a lack of specific biomarkers for M2-TAMs. Previously, we demonstrated that a novel peptide drug conjugate (TB511) consisting of a TAM-binding peptide and the apoptosis-promoting peptide targets M2-TAMs. This was achieved through M2-TAM targeting, although the target mechanism of action remained elusive. Herein, we elucidate the anticancer efficacy of TB511 by identifying new target proteins that preferentially bind to M2-TAMs and clarifying the apoptosis-inducing mechanism in these cells.

We investigated the target proteins and binding site of TB511 using LC-MS/MS analyses, surface plasmon resonance and peptide-protein interaction 3D modeling. Activated CD18 expression in M2 TAMs was assessed using Quantibrite PE beads in PBMCs. The anticancer efficacy of TB511 was tested using colorectal cancer (CRC) and non-small cell lung cancer (NSCLC) mouse model. The immunotherapeutic effect of TB511 was investigated through spatial transcriptomics in human pancreatic ductal adenocarcinoma (PDAC) model.

Activated CD18 was highly expressed in human tumor tissues and was significantly higher in M2 TAMs than in other immune cells. TB511 showed high binding affinity to CD18 among the cell membrane proteins of M2 macrophages and appeared to bind to the cysteine-rich domain in the activated form. Moreover, TB511 specifically induced apoptosis in M2 TAMs, but its targeting ability to M2 macrophages was inhibited in CD18 blockade or knockout model. In mouse or humanized mouse models of solid tumors such as CRC, NSCLC, and PDAC, TB511 suppressed tumor growth by targeting M2-TAMs via CD18 and enhancing the presence of CD8+ T cells in the TME.

Collectively, our findings suggest that activated CD18 holds promise as a novel target protein for cancer therapy, and TB511 shows potential as a therapeutic agent for tumor treatment.

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.

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, with significant differences in incidence and outcomes between men and women. Estrogen receptor alpha (ERα) expression is associated with sex-based differences and poor prognostic outcomes in HCC. However, the detailed function of ERα in the tumor microenvironment of HCC remains unclear.

Bioinformatics analysis of differentially expressed genes in HCC samples was performed from publicly available databases, and ERα was selected. The function of ERα was examined in the cell experiments. A co-culture system was built to study function of ERα-treated liver cells on macrophages in vitro. The precise mechanism was determined using quantitative real-time PCR, western blotting, immunohistochemistry, mass spectrometry, co-immunoprecipitation, and dual-luciferase reporter assay.

ERα played an important role in the pathogenesis of sexual dimorphism in HCC. ERα mainly acted on macrophages in the tumor microenvironment (TME) of HCC and reduced M2 macrophage infiltration through CCL2. By acting on NF2 and 14-3-3theta, ERα enhanced YAP phosphorylation and attenuated the nuclear translocation of YAP, thereby suppressing CCL2 expression. It also acted as a transcription factor that regulated CCL2 expression at the transcriptional level.

ERα/YAP/CCL2 signaling reduced M2 macrophages infiltration to inhibit HCC progression, revealing the effect of ERα in cancer cells on immune cells in HCC microenvironment.

Arginine plays a critical role in colorectal cancer (CRC) progression. We find that arginine catabolism is reduced in the intestinal microbiota of patients with CRC but increased in tumor tissue. We further verify that Escherichia coli can consume arginine via the arginine succinyltransferase (AST) pathway, and gavaging mice with the AST-deficient E. coli Nissle 1917 (ΔacEcN) can inhibit arginine catabolism of the intestinal microbiota, thereby increasing the arginine concentration in the colon. In the azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced CRC mouse model, reduced arginine catabolism in the intestinal microbiota increases the arginine concentration in the tumor microenvironment, thereby activating the nitric oxide (NO) synthesis pathway and polyamine synthesis pathway in tumor tissues, stimulating angiogenesis in the tumor microenvironment, inducing M2 macrophage polarization, and activating the Wingless/Integrated (Wnt)/β-catenin pathway, ultimately accelerating CRC progression. This study reveals that intestinal microbiota can affect CRC progression through arginine catabolism, providing a potential target for the prevention and therapy of CRC.

Immunotherapy is recognized as an effective and promising treatment modality that offers a new approach to cancer treatment. However, identifying responsive patients remains challenging. Anoikis, a distinct form of programmed cell death, plays a crucial role in cancer progression and metastasis. Thus, we aimed to investigate prognostic biomarkers based on anoikis and their role in guiding immunotherapy decisions for esophageal squamous cell carcinoma (ESCC). By consensus clustering, the GSE53624 cohort of ESCC patients was divided into two subgroups based on prognostic anoikis-related genes (ARGs), with significant differences in survival outcomes between the two subgroups. Subsequently, we constructed an ARGs signature with four genes, and its reliability and accuracy were validated both internally and externally. Additional, different risk groups showed notable variances in terms of immunotherapy response, tumor infiltration, functional enrichment, immune function, and tumor mutation burden. Notably, the effectiveness of the signature in predicting immunotherapy response was confirmed across multiple cohorts, including GSE53624, GSE53625, TCGA-ESCC, and IMvigor210, highlighting its potential utility in predicting immunotherapy response. In conclusion, the ARGs signature has the potential to serve as an innovative and dependable prognostic biomarker for ESCC, facilitating personalized treatment strategies in this field, and may represent a valuable new tool for guiding ESCC immunotherapy decision-making.

Oesophageal cancer (EC) is among the most common illnesses globally, and its prognosis is unfavourable. Surgery, radiotherapy and chemotherapy are the primary therapy options for EC. Despite the occasional efficacy of these traditional treatment modalities, individuals with EC remain at a significant risk for local recurrence and metastasis. Consequently, innovative and efficacious medicines are required. In recent decades, clinical practice has effectively implemented cell therapy, which includes both stem cell and non-stem cell-based approaches, as an innovative tumour treatment, offering renewed hope to patients with oesophageal squamous cell carcinoma (ESCC). This paper examines the theoretical framework and contemporary advancements in cell treatment for individuals with EC. We further described current clinical studies and summarised essential data related to survival and safety assessments.

Efficient cutaneous wound healing requires a coordinated transition between inflammatory phases mediated by dynamic changes in leukocyte subset populations. Here, we identify STING as a key innate immune mediator governing timely resolution of inflammation by regulating macrophage dynamics during skin repair. Using a mouse model, we show STING deficiency caused delayed wound closure associated with abnormal persistence of TNF-α+ leukocytes. This resulted from the impaired macrophage recruitment. STING controlled the trafficking of bone marrow myeloid cells into blood and wounds, intrinsically enhancing macrophage migratory capacity through STAT3 activation. Specifically, STING modulated the production of monocyte chemokines and their receptors CCR2/CCR5 to enable efficient egress and wound infiltration. Consequently, disrupted systemic and local STING-STAT3-chemokine signaling combine to delay macrophage influx. This study elucidates STING as a critical rheostat tuning macrophage responses through STAT3 to orchestrate inflammatory resolution necessary for efficient wound healing. Our findings have broad implications for targeting STING therapeutically in both regenerative medicine and inflammatory disease contexts.

Esophageal carcinoma (ESCA) is a highly malignant tumor with the highest incidence in Eastern Asia. Although treatment modalities for ESCA have advanced in recent years, the overall prognosis remains poor, as most patients are diagnosed at an advanced stage of the disease. There is an urgent need to promote early screening for ESCA to increase survival rates and improve patient outcomes. The development of ESCA is closely linked to the complex tumor microenvironment (TME), where chemokines and their receptors play pivotal roles. Chemokines are a class of small-molecule, secreted proteins and constitute the largest family of cytokines. They not only directly regulate tumor growth and proliferation but also influence cell migration and localization through specific receptor interactions. Consequently, chemokines and their receptors affect tumor invasion and metastatic spread. Furthermore, chemokines regulate immune cells, including macrophages and regulatory T cells, within the TME. The recruitment of these immune cells further leads to immunosuppression, creating favorable conditions for tumor growth and metastasis. This review examines the impact of ESCA-associated chemokines and their receptors on ESCA, emphasizing their critical involvement in the ESCA TME.

Tumor-infiltrating macrophages, known as tumor-associated macrophages, play a crucial role in the tumor microenvironment. Herein, immunohistochemistry revealed that intratumoral CD68-positive macrophages are associated with poor prognosis and clinicopathologic factors in patients with hepatocellular carcinoma (HCC). Subsequently, an indirect co-culture system involving HCC cells and peripheral blood-derived macrophages was developed. cDNA microarray analysis revealed that chemokine (C-C motif) ligand 2 (CCL2) was highly expressed in HCC cells co-cultured with macrophages. CCL2 neutralization suppressed proliferation, migration, and phosphorylation of extracellular signal-regulated kinase (Erk) in HCC cells and macrophages enhanced through co-culture. In contrast, recombinant human CCL2 (rhCCL2) addition facilitated these malignant phenotypes and increased Erk phosphorylation levels in HCC cells and macrophages. The primary CCL2 receptor, CCR2, was expressed in HCC cells and macrophages and was up-regulated in co-cultured HCC cells. CCR2 inhibition suppressed malignant phenotypes and reduced phosphorylated levels of Erk enhanced by rhCCL2. Additionally, the inhibition of Erk signal suppressed rhCCL2-enhanced malignant phenotypes. Moreover, serum CCL2 levels were higher in patients with HCC than those in healthy donors. On the basis of immunohistochemistry, CCL2-positive cases with high CCR2 expression and phosphorylated Erk-positive cases exhibited poor survival outcomes. Therefore, CCL2 up-regulation through interactions between HCC cells and macrophages contributed to HCC progression, making the CCL2/CCR2/Erk signal a potential target for HCC treatment.

Disturbances in tumor cell metabolism reshape the tumor microenvironment (TME) and impair antitumor immunity, but the implicit mechanisms remain elusive. Here, we found that spermine synthase (SMS) was significantly upregulated in tumor cells, which correlated positively with the immunosuppressive microenvironment and predicted poor survival in hepatocellular carcinoma (HCC) patients. Via "subcutaneous" and "orthotopic" HCC syngeneic mouse models and a series of in vitro coculture experiments, we identified elevated SMS levels in HCC cells played a role in immune escape mainly through its metabolic product spermine, which induced M2 polarization of tumor-associated macrophages (TAMs) and subsequently corresponded with a decreased antitumor functionality of CD8+ T cells. Mechanistically, we discovered that spermine reprogrammed TAMs mainly by activating the PI3K-Akt-mTOR-S6K signaling pathway. Spermine inhibition in combination with immune checkpoint blockade effectively diminished tumor burden in vivo. Our results expand the understanding of the critical role of metabolites in regulating cancer progression and antitumor immunity and open new avenues for developing novel therapeutic strategies against HCC.

Patients with EGFR mutations exhibit immunosuppressive microenvironments, limiting responsiveness to immunotherapy. We used digital spatial profiling to analyze non-small cell lung carcinomas in 25 patients before and after EGFR tyrosine kinase inhibitor (TKI) treatment, including 14 patients treated with first-line osimertinib, focusing on CD45-positive immune regions and pan-cytokeratin-positive tumor regions. Osimertinib treatment resulted in altered angiogenic pathways and immune cell proportions, with reduced plasma cells (22.2%-11.7%; p = 0.025) and increased macrophage infiltration (p = 0.145). The most predominant immune subtypes before and after treatment was the interferon-γ (IFN-γ)-dominant C2 subtype and the lymphocyte-depleted C4 subtype. Two patients who showed the opposite pattern, transiting from C4 to C2, had durable responses to subsequent atezolizumab/bevacizumab/carboplatin/paclitaxel treatment. Our results shed light on the immunomodulatory effects of osimertinib treatment and suggest that co-targeting angiogenesis and anti-programmed death (ligand) 1 might be effective in EGFR-TKI-resistant non-small cell lung cancer.

Respiratory virus infection is an important cause of both community acquired pneumonia and hospital-acquired pneumonia. Various respiratory viruses, including influenza virus, avian influenza virus, respiratory syncytial virus (RSV), SARS-CoV, MERS-CoV, and SARS-CoV-2, result in severe fibrosis sequelae after the acute phase. Since the COVID-19 pandemic, respiratory virus infection, as an important cause of pulmonary fibrosis, has attracted increasing attention around the world. Respiratory virus infection usually triggers robust inflammation responses, leading to large amounts of proinflammatory mediator production, such as chemokine (C-C motif) ligand 2 (CCL2), a critical chemokine involved in the recruitment of various inflammatory cells. Moreover, CCL2 plays a pivotal role in the pathogenesis of fibrosis progression, through regulating recruitment of bone marrow-derived monocytes and increasing the expression of extracellular matrix proteins. This review provided a concise overview of the common fibrosis sequelae after virus infection. Then we discussed the elevated levels of CCL2 in various respiratory virus infection, underscoring its potent profibrotic role. Targeting the CCL2/CCR2 axis holds promise for alleviating fibrosis sequelae post-acute virus infection and warrants further investigation.

Ovarian cancer is a malignancy gynecologic oncology with high incidence and high mortality rate. M2-like tumor-associated macrophages promote cancer cell migration and metastasis. Ovarian tumor family deubiquitinase 4 (OTUD4) belongs to deubiquitinating enzyme family. The roles of OTUD4 in tumor microenvironments in ovarian cancer remains unknow. In this work, OTUD4 was overexpressed or knocked down in high-grade serous ovarian cancer cells OVCAR8 and CAOV3. Ovarian cells were co-cultured with THP-1 macrophages to simulate the tumor microenvironment. We found that OTUD4-expressed ovarian cells inhibited macrophage chemotaxis and M2 polarization. Besides, in ovarian tumor-bearing mouse model, OTUD4 suppressed tumor metastasis and remodeling tumor-associated macrophages phenotype (pro-tumor M2 to anti-tumor M1). In mechanism, OTUD4 protein bound to YAP1 protein, and downregulation of OTUD4 enhanced K63 ubiquitination and nuclear translocation of YAP1, thus increasing CCL2 transcription and subsequent macrophage recruitment. OTUD4 might inhibit CCL2 expression to regulate tumor-associated macrophages in ovarian tumor microenvironment. Those findings present a potential therapeutic strategy for ovarian cancer.

Background: Gastric cancer (GC) is one of the most common malignant tumors worldwide, with fast metastasis and high mortality rate. GC cells and tumor immune microenvironment exhibit high heterogeneity. Multiple pieces of evidence suggest that TGFβ1 intervenes in the tumor microenvironment, immune cells and GC prognosis. The aim of this study is to comprehensively investigate the functional intervention of macrophage polarization subtypes on gastric cancer cell lines in the GC tumor microenvironment, providing valuable insights into tumor microenvironment research and potential targets for treatment strategies. Methods: TCGA database and multiple GEO datasets were used to validate the role of TGFβ1 in cancer prognosis, immune infiltration and subtype macrophage polarization. Construct different subtypes of macrophages and establish cell co culture systems using Transwell chambers. Enzyme linked immunosorbent assay (ELISA), western blotting (WB) and reverse transcription quantitative polymerase chain reaction (RT-qPCR) were used to verify the changes in the metastatic function and defense mechanism of gastric cancer cells (Hgc27 and MKN45) in different co culture systems. Further analyze the effect of gastric cancer cell metabolites on macrophage subtype polarization. Results: TGFβ1 was highly expressed in GC tissues, highly expressed TGFβ1 could reduce the survival time of GC patients. The GC immune infiltration results confirmed the correlation between TGFβ1 and M2 macrophages. The GEO dataset results of gastric cancer at different stages showed that some M2 macrophage markers showed consistent changes with TGFβ1. The WB, ELISA and RT-qPCR have identified TGFβ1-induced polarization of M2c macrophages, most biomarkers are associated with M2c. M2c macrophages can enhance cell migration and function, can inhibit ferroptosis in gastric cancer cells, endowing them with stronger special environmental resistance. Gastric cancer cells tend to polarize towards M2 macrophages, with M2c being the main M2 subtype of macrophages. Conclusion: In conclusion, our study reveals a mutually beneficial symbiotic relationship between M2c macrophages and cancer cells in the microenvironment of gastric cancer tumors. TGFβ1 promotes the production of M2c macrophages, which enhance the function and ferroptosis resistance of gastric cancer cells. Gastric cancer cells provide the material basis for M2c macrophage polarization. This new evidence may provide new insights into developing more effective targeted therapies for gastric cancer to combat the formation of immune escape and metastasis in gastric cancer.

Chemokines (chemotactic cytokines) play essential roles in developmental process, immune cell trafficking, inflammation, immunity, angiogenesis, cellular homeostasis, aging, neurodegeneration, and tumorigenesis. Chemokines also modulate response to immunotherapy, and consequently influence the therapeutic outcome. The mechanisms underlying these processes are accomplished by interaction of chemokines with their cognate cell surface G protein-coupled receptors (GPCRs) and subsequent cellular signaling pathways. Chemokines play crucial role in influencing aging process and age-related diseases across various tissues and organs, primarily through inflammatory responses (inflammaging), recruitment of macrophages, and orchestrated trafficking of other immune cells. Chemokines are categorized in four distinct groups based on the position and number of the N-terminal cysteine residues; namely, the CC, CXC, CX3C, and (X)C. They mediate inflammatory responses, and thereby considerably impact aging process across multiple organ-systems. Therefore, understanding the underlying mechanisms mediated by chemokines may be of crucial importance in delaying and/or modulating the aging process and preventing age-related diseases. In this review, we highlight recent progress accomplished towards understanding the role of chemokines and their cellular signaling pathways involved in aging and age-relaed diseases of various organs. Moreover, we explore potential therapeutic strategies involving anti-chemokines and chemokine receptor antagonists aimed at reducing aging and mitigating age-related diseases. One of the modern methods in this direction involves use of chemokine receptor antagonists and anti-chemokines, which suppress the pro-inflammatory response, thereby helping in resolution of inflammation. Considering the wide-spectrum of functional involvements of chemokines in aging and associated diseases, several clinical trials are being conducted to develop therapeutic approaches using anti-chemokine and chemokine receptor antagonists to improve life span and promote healthy aging.

Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors with a high metastasis rate and a poor prognosis. ETS variant transcription factor 1 (ETV1) plays an important role in multiple malignancies. However, its function in ESCC progression and tumor microenvironment (TME) remains to be explored. In this study, we characterized the role of ETV1 in ESCC process and TME.

Gene expression and immune infiltration in ESCC samples from the Cancer Genome Atlas (TCGA) were analyzed. The expression of ETV1 in clinical samples was detected by real-time PCR, western blot and immunohistochemistry staining. Cell growth was detected by CCK-8 and colony formation assays. Macrophage phenotypes were determined using flow cytometry. Immunofluorescence double staining was used to detect the tumor-associated macrophage (TAM) infiltration. The tumor volume was recorded and weighed. Transcriptional activity was measured using dual-luciferase assay, chromatin immunoprecipitation (ChIP) assay and DNA pull-down assay.

In this study, through analysis of ESCC samples from TCGA database and the clinic, we noticed that ETV1 was highly expressed in ESCC tumor tissues and was associated with TAM infiltration. Overexpression of ETV1 promoted ESCC cell proliferation in vitro and xenograft tumor growth in nude mice, while ETV1 knockdown elicited the opposite effects. Furthermore, ETV1 upregulation in tumor tissues was found to drive M2 macrophage infiltration both in vitro (transwell assays) and in vivo (xenograft tumor models). C-C motif chemokine ligand 2 (CCL2), a key factor inducing M2 macrophage polarization, was also found to be elevated in ESCC tumor tissues. Mechanism study demonstrated that ETV1 facilitated M2 macrophage infiltration via the transcriptional modulation of CCL2. In addition, the cause of the changes in ETV1 activity and expression was investigated. The E2 small ubiquitin-like modifier (SUMO) binding enzyme UBC9 increased ETV1 activity and expression, indicating the presence of SUMO modification in ETV1.

Our data deciphered the mechanism of ETV1-mediated M2 macrophage infiltration in the TME of ESCC, which has important implications for the development of novel prognostic and therapeutic targets to optimize current therapies against ESCC.

Psoriasis is an incurable chronic inflammatory disease that requires new interventions. Here, we found that fibroblasts exacerbate psoriasis progression by promoting macrophage recruitment via CCL2 secretion by single-cell multi-omics analysis. The natural small molecule celastrol was screened to interfere with the secretion of CCL2 by fibroblasts and improve the psoriasis-like symptoms in both murine and cynomolgus monkey models. Mechanistically, celastrol directly bound to the low-density lipoprotein receptor-related protein 1 (LRP1) β-chain and abolished its binding to the transcription factor c-Jun in the nucleus, which in turn inhibited CCL2 production by skin fibroblasts, blocked fibroblast-macrophage crosstalk, and ameliorated psoriasis progression. Notably, fibroblast-specific LRP1 knockout mice exhibited a significant reduction in psoriasis like inflammation. Taken together, from clinical samples and combined with various mouse models, we revealed the pathogenesis of psoriasis from the perspective of fibroblast-macrophage crosstalk, and provided a foundation for LRP1 as a novel potential target for psoriasis treatment.

By inducing apoptosis, promoting differentiation and reducing the migration of cancer cells, arsenic has a higher therapeutic effect and lower risk of recurrence and metastasis than conventional anticancer drugs. However, the low bioavailability and adverse side effects of arsenic hinder its application in hepatocellular carcinoma (HCC). Therefore, a M1 macrophage membrane-coated nickel-arsenic/polydopamine nanocomplex (NiAsOx@P@M) was constructed to enhance the combined antitumor effects of chemotherapy and immunotherapy. The nanocomplex consisted of a nickel-arsenic oxide core, a polydopamine (PDA) shell and a M1 macrophage membrane (MM) coating. MM endowed the nanocomplex with natural tumor homing and immune escape properties, and the nanocomplex was gradually accumulated in the tumor tissue during the internal circulation. The acid response of PDA led to its degradation in the tumor microenvironment (TME). The degradation product dopamine (DA) and MM jointly promoted tumor immunity and regulated tumor-associated macrophages (TAMs) to repolarization M1 phenotype. The nickel-arsenic oxide core dissociated in an acid environment and released arsenic, thus killing tumor cells. In summary, the nanocomplex provided a promising delivery strategy for arsenic therapy of HCC and a novel design idea for the conversion of inorganic drugs into organic preparations.

Esophageal squamous cell carcinoma (ESCC) patients often face a grim prognosis due to lymph node metastasis. However, a comprehensive understanding of the cellular and molecular characteristics of metastatic lymph nodes in ESCC remains elusive. In this study involving 12 metastatic ESCC patients, we employed single-cell sequencing, spatial transcriptomics (ST), and multiplex immunohistochemistry (mIHC) to explore the spatial and molecular attributes of primary tumor samples, adjacent tissues, metastatic and non-metastatic lymph nodes. The analysis of 161,333 cells revealed specific subclusters of epithelial cells that were significantly enriched in metastatic lymph nodes, suggesting pro-metastatic characteristics. Furthermore, stromal cells in the tumor microenvironment, including MMP3+IL24+ fibroblasts, APLN+ endothelial cells, and CXCL12+ pericytes, were implicated in ESCC metastasis through angiogenesis, collagen production, and inflammatory responses. Exhausted CD8+ T cells in a cycling status were notably prevalent in metastatic lymph nodes, indicating their potential role in facilitating metastasis. We identified distinct cell-cell communication networks and specific ligand-receptor pathways. Our findings were validated through a spatial transcriptome map and mIHC. This study enhances our comprehension of the cellular and molecular aspects of metastatic lymph nodes in ESCC patients, offering potential insights into novel therapeutic strategies for these individuals.

The disease burden of renal cell carcinoma (RCC) has decreased in recent years with advances in treatment, but its pathogeny still remains elusive. We aim to study the role of homeobox A3 (HOXA3)/ubiquitin-specific peptidase 15 (USP15)/SQSTM1 axis on autophagy and M2-type macrophage polarization in RCC. In this study, cell apoptosis and proliferation were assessed by flow cytometry and CCK-8. Autolysosome fusion was observed by immunofluorescence detection of LC3 and LAMP2. The binding between HOXA3 and USP15 promoter was tested by chromatin immunoprecipitation (ChIP), EMSA, and dual-luciferase reporter assays. Also, the interaction between deubiquitinated enzyme (DUB) USP15 and SQSTM1, and ubiquitinated level of SQSTM1 were determined by co-immunoprecipitation (Co-IP) assay. Expression levels of HOXA3, USP15, C-C motif chemokine 2 (CCL2), CCL2 receptor (CCR2), M2-type macrophages, and autophagy-related markers were measured by Western blot, quantitative reverse transcription PCR (RT-qPCR), ELISA, and immunohistochemistry. Role of HOXA3/USP15 axis was verified by xenograft tumor experiment in vivo. We showed upregulated HOXA3 in RCC tissues and cells, and RCC tissues with metastasis showed higher HOXA3 level. The higher HOXA3 expression was relevant to worse overall survival in patients with RCC. HOXA3 induced RCC cell proliferation, and suppressed autophagy and apoptosis via transcriptionally activating USP15 expression. USP15 then induced deubiquitination modification of SQSTM1 in RCC cells. SQSTM1 supported M2-type macrophage polarization by inducing CCL2 secretion. HOXA3 or USP15 knockdown suppressed tumor growth and M2-type macrophage infiltration in vivo. In conclusion, HOXA3 transcriptionally activates USP15 expression, and upregulated USP15 facilitates the deubiquitination of SQSTM1 in RCC. This process on the one hand suppresses autophagy, on the other hand increases M2-type macrophage polarization through stimulating the secretion of CCL2.NEW & NOTEWORTHY We report a novel finding that highly expressed homeobox A3 (HOXA3) transcriptionally activates the expression of ubiquitin-specific peptidase 15 (USP15), resulting in the promotion of deubiquitination of SQSTM1. This process on the one hand suppresses autophagy in renal cell carcinoma (RCC), on the other hand increases M2-type macrophage polarization in the tumor microenvironment through stimulating the secretion of C-C motif chemokine 2 (CCL2).