Tumor-associated macrophages (TAMs) are closely associated with tumor development and patient outcomes due to their plasticity and polarization capacity. Several distinct TAMs have been proposed, but a complete understanding of heterogeneity and differentiation spectrum of macrophage in human primary liver cancer remains elusive.

Deep single-cell RNA sequencing (scRNA-seq) data from 19 primary liver cancer patients were used to profile the transcriptomes of TAMs in liver cancer. Ingenuity pathway analysis (IPA) and in vitro experiments were used to explore possible mechanisms responsible for related signaling pathways altered at the transcriptional level. Finally, we analyzed the relationship between the abundance of the TAMs and the survival outcomes of the 428 patients in the Cancer Genome Atlas (TCGA).

Transcriptional profiles allowed us to identify four distinct TAMs cell subsets based on molecular and functional properties and to reconstruct their developmental trajectory. Specifically, TAM_c4 was preferentially enriched and potentially expanded in the advanced-stage patients or those receiving immune checkpoint blockade therapy (ICT). Gene pathway analysis revealed aberrant TGFB1 activation in TAM_c4, which was experimentally confirmed to drive TAM phenotypic transitions via autophagy signaling. High abundance of TAM_c4 is found to be related to a short survival time and low abundance of CD8+ T cells in primary liver cancers.

This integrated transcriptome compendium and experimental validation offer both mechanistic insights and a resource for understanding TAM heterogeneity in primary liver cancers.

Over the last decade, immune checkpoint inhibitors (ICIs) like PD-1/PD-L1 or CTLA-4, which reinvigorate T cells for tumor control have become standard-of-care treatment options. In response to the increasingly recognized mechanisms of resistance to T cell activation in immunologically cold tumors, immuno-oncology drug development has started to shift beyond T cell approaches. These include tumor-associated macrophages (TAMs), a major pro-tumor immune cell population in the tumor microenvironment known to silence immune responses.

Here we outline anti-TAM therapies in current development, either as monotherapy or in combination with other treatment modalities. We describe emerging drugs targeting TAMs under investigation in phase II and III testing with a focus on their distinguishing mechanism of action which include (1) reprogramming of TAMs toward anti-tumor function and immune surveillance, (2) blockade of recruitment, and (3) reduction and ablation of TAMs.

Several new immuno-oncology agents are under investigation to harness anti-tumor functions of TAMs. While robust anti-tumor efficacy of anti-TAM therapies across advanced solid organ cancers remains elusive to-date, TAM reprogramming therapies have yielded benefits in select cancers. The inherent heterogeneity of the diverse TAM population will require enhanced investments into biomarker-driven approaches to fully leverage its therapeutic potential.

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.

Glioblastoma is the most aggressive primary brain tumor, with a median survival of 15 months with treatment. Standard-of-care (SOC) consists of resection, radio- and chemotherapy. Clinical trials involving PD-1 inhibition with nivolumab combined with SOC failed to increase survival. A quantitative understanding of the interactions between the tumor and its immune environment that drive treatment outcomes is currently lacking. As such, we developed a mathematical model of tumor growth that considers CD8+ T cells, pro- and antitumoral tumor-associated macrophages and microglia (TAMs), SOC, and nivolumab. Using our model, we studied five TAM-targeting strategies currently under investigation for solid tumors. Our results show that PD-1 inhibition fails due to a lack of CD8+ T cell recruitment during treatment, explained by TAM-driven immunosuppressive mechanisms. Our model predicts that while reducing TAM numbers does not improve prognosis, altering their functions to counter their protumoral properties has the potential to considerably reduce post-treatment tumor burden. In particular, restoring antitumoral TAM phagocytic activity through anti-CD47 treatment in combination with SOC was predicted to nearly eradicate the tumor. By studying time-varying efficacy with the same half-life as the anti-CD47 antibody Hu5F9-G4, our model predicts that repeated dosing of anti-CD47 provides sustained control of tumor growth. We propose that targeting TAMs by enhancing their antitumoral properties is a highly promising avenue to treat glioblastoma and warrants future clinical development. Together, our results provide proof-of-concept that mechanistic mathematical modeling can uncover the mechanisms driving treatment outcomes and explore the potential of novel treatment strategies for hard-to-treat tumors like glioblastoma.

Macrophages are heterogeneous cells that are the mediators of tissue homeostasis. These immune cells originated from monocytes and are classified into two basic categories, M1 and M2 macrophages. M1 macrophages exhibit anti-tumorous inflammatory reactions due to the behavior of phagocytosis. M2 macrophages or tumor-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment (TME) and have a basic role in tumor progression by interacting with other immune cells in TME. By the expression of various cytokines, chemokines, and growth factors, TAMs lead to strengthening tumor cell proliferation, angiogenesis, and suppression of the immune system which further support invasion and metastasis. This review discusses recent and updated mechanisms regarding tumor progression by M2 macrophages. Moreover, the current therapeutic approaches targeting TAMs, their advantages, and limitations are also summarized, and further treatment approaches are outlined along with an elaboration of the tumor regression role of macrophages. This comprehensive review article possibly helps to understand the mechanisms underlying the tumor progression and regression role of macrophages in a comparative way from a basic level to the advanced one.

It has been shown that the Basal cell carcinoma (BCC) is associated with chronic inflammation of skin conditions, the circulating inflammatory protein levels may be a more intuitive index in response to inflammation, however, the cause-and-effect relationship between circulating inflammatory proteins and BCC is currently unknown.

This study performed a Mendelian randomization (MR) analysis using the plasma inflammatory protein levels from a large genome-wide protein quantitative trait loci study as the exposure data, and the outcome data from a GWAS for BCC. Inverse variance weighed, MR-Egger, maximum likelihood ratio, and weighted median for assessing causality between inflammatory proteins and BCC. MR-Egger regression and Cochran's Q statistic were applied for sensitivity analysis and MRPRESSO was applied to exclude outliers. Inverse MR analysis was performed on inflammatory proteins found to be causally associated with BCC.

Six circulating inflammatory proteins with a causal relationship with BCC were obtained, including CCL4, was of a significant protective effect on BCC development. IL-18 and CCL28, were of suggestive protective effects on BCC development. CX3CL1, IL-17A, and CSF-1 were potential risk factors in the development of BCC. According to the results of reverse MR analysis, there is no significant causal relationship between BCC and the above-mentioned inflammatory proteins.

This two-sample MR study revealed a strong association between circulating inflammatory proteins and the development of BCC. Specifically, CCL4, CCL28, IL-18, CX3CL1, IL-17A, and CSF-1 emerged as potential targets for prognostic evaluation and treatment of BCC. However, further experimental studies are needed to elucidate the specific mechanisms.

Macrophages are immune cells belonging to the mononuclear phagocyte system. They play crucial roles in immune defense, surveillance, and homeostasis. This review systematically discusses the types of hematopoietic progenitors that give rise to macrophages, including primitive hematopoietic progenitors, erythro-myeloid progenitors, and hematopoietic stem cells. These progenitors have distinct genetic backgrounds and developmental processes. Accordingly, macrophages exhibit complex and diverse functions in the body, including phagocytosis and clearance of cellular debris, antigen presentation, and immune response, regulation of inflammation and cytokine production, tissue remodeling and repair, and multi-level regulatory signaling pathways/crosstalk involved in homeostasis and physiology. Besides, tumor-associated macrophages are a key component of the TME, exhibiting both anti-tumor and pro-tumor properties. Furthermore, the functional status of macrophages is closely linked to the development of various diseases, including cancer, autoimmune disorders, cardiovascular disease, neurodegenerative diseases, metabolic conditions, and trauma. Targeting macrophages has emerged as a promising therapeutic strategy in these contexts. Clinical trials of macrophage-based targeted drugs, macrophage-based immunotherapies, and nanoparticle-based therapy were comprehensively summarized. Potential challenges and future directions in targeting macrophages have also been discussed. Overall, our review highlights the significance of this versatile immune cell in human health and disease, which is expected to inform future research and clinical practice.

Macrophages are key tumor microenvironment (TME) regulators, exhibiting remarkable plasticity that enables them to either suppress or promote cancer progression. Emerging evidence highlights the critical role of macrophage-derived long non-coding RNAs (lncRNAs) in shaping tumor immunity, influencing macrophage polarization, immune evasion, angiogenesis, metastasis, and therapy resistance. This review comprehensively elucidates the functional roles of M1- and M2-associated lncRNAs, detailing their molecular mechanisms and impact on cancer pathogenesis. In summary, elucidating the roles of lncRNAs derived from macrophages in cancer progression offers new avenues for therapeutic strategies, significantly improving patient outcomes in the fight against the disease. Further research into the functional significance of these lncRNAs and the development of targeted therapies is essential to harness their potential fully in clinical applications. We further explore their potential as biomarkers for cancer prognosis and therapeutic targets for modulating macrophage activity to enhance anti-cancer immunity. Targeting macrophage-derived lncRNAs represents a promising avenue for precision oncology, offering novel strategies to reshape the TME and improve cancer treatment outcomes.

An understanding of the tumor immune microenvironment is required to improve treatment, especially the selection of immune checkpoint inhibitors (ICIs). In this study, we stratified the immunotypes of tongue squamous cell carcinoma (TSCC) based on the results of comprehensive immune profiling.

We enrolled 87 therapy-naïve TSCC and 17 ICI-treated TSCC patients who underwent glossectomy without any other prior therapy. Comprehensive immune profile analyses employed multiplex immunofluorescence and tissue imaging.

Based on the hierarchies of 58 immune parameters and the spatial distances between cytotoxic T lymphocytes (CTL) and tumor cells, we stratified five immunotypes: Immunoactive type I, border type II, immunosuppressed type III, immunoisolating type IV, and immunodesert type V. The type I frequency was only 16%. Most TSCCs (~ 70%) were of types III-V. The CTL density (CTL-D) was closely correlated with the PD-L1+ pan-macrophages (panM)-D, and the panM-D closely correlated with the PD-1+ CTL-D. This indicated that PD-1 and PD-L1 expression required macrophages and CTL recruitment in the tumor microenvironment. No ICI-treated TSCC patients, all of whom were recurrent/metastatic cases, were of the type I immunotype, and almost half (47.0%) were of the immunodesert type V. Most cases exhibited an imbalance between T-cell PD-1 and macrophage PD-L1 expression.

We defined five TSCC-specific immunotypes based on the results of comprehensive immune profiling analyses. Immunoactive type, which would be sensitive to ICI monotherapy, was rare, and most TSCC cases exhibited immune-regulated immunotypes. Immunotype-based personalized treatments are required to improve clinical outcomes.

Therapeutic depletion of immunosuppressive regulatory T cells (Treg) may overcome resistance to cancer immunotherapies. RG6292 is an anti-CD25 antibody that preferentially depletes Tregs while preserving effector T-cell functions in preclinical models. The safety, pharmacokinetics, pharmacodynamics, and antitumor efficacy of selective Treg depletion by RG6292 administered as monotherapy or in combination with atezolizumab were evaluated in two phase I studies.

Adult patients with advanced solid tumors were administered intravenous RG6292, given every 3 weeks alone (study 1: NCT04158583, n = 76) or with 1,200 mg atezolizumab every 3 weeks (study 2: NCT04642365, n = 49). Both studies included dose escalation and expansion parts to determine the maximum tolerated dose and recommended phase II dose.

RG6292 was well tolerated. Pruritus and rash were the most frequent adverse events and were manageable with supportive treatment. Serum RG6292 levels increased dose proportionally, independent of the atezolizumab combination. RG6292 induced a sustained dose-dependent depletion of peripheral Tregs with no apparent effect on other immune cells. Evidence of intratumoral Treg reduction (≥50% vs. baseline) was observed at RG6292 doses of 35 to 100 mg. The maximum tolerated dose was 165 mg every 3 weeks, and the recommended phase II dose was proposed as 70 mg every 3 weeks. Objective responses were limited to three partial responses in patients receiving RG6292 combined with atezolizumab.

RG6292 induced a dose-dependent peripheral blood and measurable intratumoral Treg depletion in concordance with the proposed mode of action; however, clinical efficacy as a single agent or combined with atezolizumab was insufficient to warrant further exploration in this population.

RG6292 (vopikitug) targets CD25 (IL-2Rα) and mediates regulatory T-cell depletion while not interfering with IL-2 signaling. Peripheral and intratumoral Treg depletion was shown in two phase I studies. However, RG6292 alone or in combination with atezolizumab was insufficient to reverse and rescue from established resistance mechanisms in solid tumors.

Tenosynovial giant cell tumor is a non-malignant primary locally aggressive articular disease that affects the synovium of joints, tendon sheaths, and bursae. It is characterized by a translocation t (1;2), leading to the overexpression of CSF1 in the tumor microenvironment. CSF1 induces the recruitment of non-malignant cells, mainly macrophages, followed by the differentiation and polarization of these cells into the M2 phenotype. Surgery, particularly total synovectomy, remains the cornerstone of TGCT management. However, recurrence rates vary, reaching 40 to 60% in diffuse disease, often resulting in progressive joint dysfunction, pain, and potential need for joint replacement or limb amputation. Systemic therapy is recommended in recurrent TGCT in patients not amenable to additional surgery. Targeting the CSF1/CSF1R axis has successfully improved tumor responses and enhanced symptomatic function. In this review, we aim to explore contemporary paradigms in inoperable TGCT patients, with a focus on the physiopathology, clinical efficacy, and safety of CSF1 or CSF1R inhibitors.

Cancer cells grow and survive in the tumor microenvironment, which is a complicated process. As a key part of how colorectal cancer (CRC) progresses, tumor-associated macrophages (TAMs) exhibit a double role. Through angiogenesis, this TAM can promote the growth of cancers. Although being able to modify and adjust immune cells is a great advantage, these cells can also exhibit anti-cancer properties including direct killing of cancer cells, presenting antigens, and aiding T cell-mediated responses. The delicate regulatory mechanisms between the immune system and tumors are composed of a complex network of pathways regulated by several factors including hypoxia, metabolic reprogramming, cytokine/chemokine signaling, and cell interactions. Decoding and figuring out these complex systems become significant in building targeted treatment programs. Targeting TAMs in CRC involves disrupting chemokine signaling or adhesion molecules, reprogramming them to an anti-tumor phenotype using TLR agonists, CD40 agonists, or metabolic modulation, and selectively removing TAM subsets that promote tumor growth. Multi-drug resistance, the absence of an accurate biomarker, and drug non-specificity are also major problems. Combining macrophage-targeted therapies with chemotherapy and immunotherapy may revolutionize treatment. Macrophage studies will advance with new technology and multi-omics methodologies to help us understand CRC and build specific and efficient treatments.

Over the last two decades, advancements in deciphering the intricate interactions between oncology and immunity have fueled a meteoric rise in immunotherapy for non-small cell lung cancer, typified by an explosive growth of immune checkpoint inhibitors. However, resistance to immunotherapy remains inevitable. Herein we unravel the labyrinthine mechanisms of resistance to immunotherapy, characterized by their involvement of nearly all types of cells within the body, beyond the extrinsic cancer cells, and importantly, such cells are not only (inhibitory or excitatory, or both) signal recipients but also producers, acting in a context-dependent manner. At the molecular level, these mechanisms underlie genetic and epigenetic aberrations, which are regulated by or regulate various protein kinases, growth factors, and cytokines with inherently dynamic and spatially heterogeneous properties. Additionally, macroscopic factors such as nutrition, comorbidities, and the microbiome within and around organs or tumor cells are involved. Therefore, developing therapeutic strategies combined with distinct action informed by preclinical, clinical, and real-world evidence, such as radiotherapy, chemotherapy, targeted therapy, antibody-drug conjugates, oncolytic viruses, and cell-based therapies, may stand as a judicious reality, although the ideality is to overcome resistance point-by-point through a novel drug. Notably, we highlight a realignment of treatment aims, moving the primary focus from eliminating cancer cells -- such as through chemotherapy and radiotherapy -- to promoting immune modulation and underscore the value of regulating various components within the host macro- or micro-environment, as their effects, even if seemingly minimal, can cumulatively contribute to visible clinical benefit when applied in combination with ICIs. Lastly, this review also emphasizes the current hurdles scattered throughout preclinical and clinical studies, and explores evolving directions in the landscape of immunotherapy for NSCLC.

Mucosal head and neck squamous cell carcinoma (HNSCC) is often diagnosed at an advanced stage, where the prognosis is poor due to the high rates of recurrence and metastasis. With approximately one million new cases projected in 2024, worldwide mortality of HNSCC is estimated to reach 50% of detected cases the same year. Patients with early-stage tumours showed a 50-60% five-year survival rate in the US. Immune checkpoint inhibitors (ICIs) have shown promising results in prolonging survival in a subset of patients with recurrent or metastatic disease. However, challenges remain, particularly the limited efficacy of PD-1/PD-L1 blockade therapies. PD-L1 protein expression has been shown to be limited in its predictive power for ICI therapies. Emerging evidence shows that intricate characterisation of the tumour microenvironment (TME) is fundamental to understand interacting cells. This study aims to bridge the gap in understanding the tumor microenvironment by identifying distinct spatial patterns of PD-1/PD-L1 interactions and their association with immunotherapy responses in head and neck squamous cell carcinoma (HNSCC).

In this study, we sought to apply a more nuanced approach to understanding cellular interactions by mapping PD-1/PD-L1 interactions across whole-slide HNSCC tissue samples collected prior to ICI therapy. We used a combination of spatial proteomics (Akoya Biosciences) and an in situ proximity ligation assay (isPLA, Navinci Diagnostics) to visualise PD-1/PD-L1 interactions across cell types and cellular neighbourhoods within the tumour TME.

Our findings indicate the existence of isPLA+ PD-1/PD-L1 interactions between macrophages/CD3 T cell-enriched neighbourhoods and tumour cells at the tumour-stroma boundaries in ICI-resistant tumours. The presence of these dense macrophage-tumour layers, which are either absent or dispersed in responders, indicates a barrier that may restrict immune cell infiltration and promote immune escape mechanisms. In contrast, responders had abundant B and T cell aggregates, predominantly around the tumour edges linked to enhanced immune responses to ICI therapy and better clinical outcomes.

This study highlights the utility of isPLA in detecting distinct tumour-immune interactions within the TME, offering new cellular interaction metrics for stratifying and optimising immunotherapy strategies.

Macrophage plays an important role in homeostasis and immunity, and dysfunctional macrophage polarization is believed to be associated with the pathogenesis of tissue fibrosis and tumor progression. Colony stimulating factor-1 (CSF-1), a polypeptide chain cytokine, through its receptor (CSF-1R) regulates the differentiation of macrophages. Recently, the promising therapeutic potential of CSF-1/CSF-1R signaling pathway inhibition in cancer treatment is widely used. Furthermore, inhibition of CSF-1/CSF-1R signaling combined with radiotherapy has been extensively studied to reduce immunosuppression and promote abscopal effect. In addition, cumulative evidence demonstrated that M2 phenotype macrophage is dominant in tissue fibrosis and the inhibition of CSF-1/CSF-1R signaling pathway ameliorated pulmonary fibrosis, including radiation-induced lung fibrosis. Herein, we provide a comprehensive review of the CSF-1/CSF-1R signaling pathway in radiotherapy, with a focus on advances in macrophage-targeted strategies in the treatment of cancer and pulmonary fibrosis.

Hepatocellular carcinoma (HCC) is one of the most common types of primary liver cancer and remains a leading cause of cancer-related deaths worldwide. While traditional approaches like surgical resection and tyrosine kinase inhibitors struggle against the tumor's immune evasion, monoclonal antibody (mAb)-based immunotherapies have emerged as promising alternatives. Several therapeutic antibodies that counter the immunosuppressive tumor microenvironment have demonstrated efficacy in clinical trials, leading to FDA approvals for advanced HCC treatment. A crucial aspect of advancing these therapies lies in understanding the structural interactions between antibodies and their targets. Recent findings indicate that mAbs and bispecific antibodies (bsAbs) can target different, non-overlapping epitopes on immune checkpoints such as PD-1 and CTLA-4. This review delves into the epitope-paratope interactions of structurally unresolved mAbs and bsAbs, and discusses the potential for combination therapies based on their non-overlapping epitopes. By leveraging this unique feature, combination therapies could enhance immune activation, reduce resistance, and improve overall efficacy, marking a new direction for antibody-based immunotherapy in HCC.

Although immunotherapy has achieved great progress in advanced triple-negative breast cancer (TNBC), there are still numerous patients who do not benefit from immunotherapy. Therefore, identification of the key molecule that induces immune escape and clarification of its specific mechanism in TNBC are urgently needed.

In this research, single cell sequencing and bulk sequencing were conducted for biomarker screening. Immunohistochemistry, multiplex immunofluorescence, and orthotopic TNBC tumor model were applied in identifying the key molecule driving immune escape. At the mechanical level, RNA sequencing, in vitro co-culturing system, flow cytometry, Western blotting, ELISA, and real-time qPCR were carried out.

Mortality factor 4 like 2 (MORF4L2) expression is significantly up-regulated among patients who developed anti-PD1 resistance. MORF4L2 enhances anti-PD1 resistance by inducing the chemotaxis of macrophage infiltration and promoting their polarization towards the alternative activation phenotype (M2), thus creating an immunosuppressive microenvironment. Mechanistically, MORF4L2 actes as part of NuA4 histone acetyltransferase (HAT) complex, contributes to to histone 4 lysine 12 acetylation (H4K12Ac) and activates the downstream transcription of macrophage colony-stimulating factor (CSF1). CSF1 is secreted by tumor cells and binds to the macrophage-surface CSF1 receptor (CSF1R), which chemotactically converted and polarized macrophages to the M2 phenotype. Furthermore, we revealed that grainyhead like transcription factor 2 (GRHL2) could promote MORF4L2 transcription by binding to the MORF4L2 enhancer region. Notably, BLZ549, an inhibitor of CSF1R, restored the anti-PD1 sensitivity by blocking the GRHL2/MORF4L2/H4K12Ac/CSF1 axis.

GRHL2/MORF4L2/H4K12Ac/CSF1 axis plays an important role in anti-PD1 resistance. CSF1R inhibitors can reverse GRHL2/MORF4L2-mediated anti-PD1 resistance.

The unsatisfactory immunotherapeutic responses are primarily attributed to the insufficient immune recognition and the presence of an immunosuppressive tumor microenvironment (ITM). This study focuses on the development of a tricomponent immunoactivating nanomedicine called TIN that combines a photosensitizer, an inhibitor of epidermal growth factor receptor (EGFR) and a CSF-1R inhibitor to enable photodynamic immunotherapy by downregulating PD-L1 expression and repolarizing tumor-associated macrophages (TAMs). TIN is designed to facilitate the drug delivery and target specific pathways involved in tumor progression. By inhibiting the activity of EGFR and CSF-1R, TIN reduces PD-L1 expression on tumor cells and induces the TAMs polarization to M1 phenotype, restoring the immune recognition of T cells and the phagocytosis of macrophage to reshape the immunosuppressive microenvironment. Additionally, the photodynamic therapy (PDT) of TIN can greatly destroy the primary tumor and trigger immunogenic cell death (ICD). Importantly, the immune checkpoint blockade effect of TIN can enhance the immune response of PDT-induced ICD for metastatic tumor treatment. This study presents a self-assembling strategy for the development of an all-in-one nanomedicine, effectively integrating multiple therapeutic modalities to provide a comprehensive and systemic approach for tumor suppression.

Hepatocellular carcinoma (HCC) is a major global health issue characterized by poor prognosis and complex tumor biology. One of the critical components of the HCC tumor microenvironment (TME) is tumor-associated macrophages (TAMs), which play a pivotal role in modulating tumor growth, immune evasion, and metastasis. Macrophages are divided into two major subtypes: pro-inflammatory M1 and anti-inflammatory M2, both of which may exist in TME with altered function and proportion. The anti-inflammatory M2 macrophages are further subdivided into four distinct immune suppressive subsets. TAMs are generally counted as M2-like macrophages with altered immune suppressive functions that exert a significant influence on both cancer progression and the ability of tumors to escape immune surveillance. Their involvement in modulating immune responses via different mechanisms at the local and systemic levels has made them a key target for therapeutic interventions seeking to enhance treatment outcomes. How TAMs' depletion influences immune responses in cancer is the primary interest in cancer immunotherapies. The purpose of this review is to delve into the recent progress made in TAM-targeting therapies. We will explore the current theories, benefits, and challenges associated with TAMs' depletion or inhibition. The manuscript concludes with future directions and potential implications for clinical practice.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant tumors. Macrophages are abundant in the tumor microenvironment, making them an attractive target for therapeutic intervention. While current immunotherapies, including immune checkpoint inhibition (ICI) and chimeric antigen receptor T (CAR-T) cells, have shown limited efficacy in pancreatic cancer, a novel approach involving chimeric antigen receptor macrophages (CAR-M) has, although promising, not been explored in pancreatic cancer. In this study, we first investigated the role of CAR-M cells targeting c-MET in pancreatic cancer.

The effectiveness and rationality of c-MET as a target for CAR-M in pancreatic cancer were validated through bioinformatic analyses and immunohistochemical staining of samples from pancreatic cancer patients. We utilized flow cytometry and bioluminescence detection methods to demonstrate the specific binding and phagocytic killing effect of CAR-M on pancreatic cancer cells. Additionally, we observed the process of CAR-M engulfing pancreatic cancer cells using confocal microscopy and a long-term fluorescence live cell imaging system. In an in situ tumor model transplanted into NOD/SCID mice, we administered intraperitoneal injections of CAR-M to confirm its inhibitory function on pancreatic cancer. Furthermore, we validated these findings in human monocyte-derived macrophages (hMDM).

Bioinformatics and tumor tissue microarray analyses revealed significantly higher expression levels of c-MET in tumor tissues, compared to the paired peritumoral tissues, and higher c-MET expression correlated with worse patient survival. CAR-M cells were engineered using human monocytic THP-1 cell line and hMDM targeting c-MET (CAR-M-c-MET). The CAR-M-c-MET cells demonstrated highly specific binding to pancreatic cancer cells and exhibited more phagocytosis and killing abilities than the pro-inflammatory polarized control macrophages. In addition, CAR-M-c-MET cells synergized with various cytotoxic chemotherapeutic drugs. In a NOD/SCID murine model, intraperitoneally injected CAR-M-c-MET cells rapidly migrated to tumor tissue and substantially inhibited tumor growth, which did not lead to obvious side effects. Cytokine arrays and mRNA sequencing showed that CAR-M-c-MET produced higher levels of immune activators than control macrophages.

This study provides compelling evidence for the safety and efficacy of CAR-M therapy in treating pancreatic cancer. The results demonstrate that CAR-M-c-MET significantly suppresses pancreatic cancer progression and enhances the effectiveness of cytotoxic chemotherapy. Remarkably, no discernible side effects occur. Further clinical trials are warranted in human pancreatic cancer patients.

Bladder cancer (BC) is the ninth most common and "expensive" cancer in the world. Despite the availability of various treatment modalities such as chemotherapy, immunotherapy and surgery, the overall survival rate of patients with advanced bladder cancer remains low. As one of the most abundant infiltrating immune cells in bladder cancer, tumor-associated macrophages (TAMs) play an important role in the development of BC and in the standard regimen of intravesical BCG therapy. Targeting TAMs have achieved excellent results in clinical trials for a variety of other cancers, but few studies have been conducted for bladder cancer. Further exploration is still needed to develop TAM-related therapeutic strategies for BC treatment, which are expected to improve the therapeutic efficacy and life quality of patients. This review summarizes the relationship between TAMs in bladder cancer and disease staging, evolution, patient prognosis, and treatment outcome. Several potential TAM targets in BC are also pointed, which may help to inhibit tumor-promoting TAMs and provide new therapeutic approaches for advanced BC.

Tumor-associated macrophages (TAM), a major component of the tumor microenvironment, play key roles in tumor formation and progression; however, mechanisms underlying TAM-induced tumor progression are complex and not well known. We previously reported that tumor cell-derived angiopoietin-like protein 2 (ANGPTL2) functions as a tumor promoter in some cancer contexts.

We examined ANGPTL2 expression in paraffin-embedded tumor samples from resected specimens of 221 patients with esophageal cancer. Patients were subdivided into four groups based on immunohistochemistry scores described above: ANGPTL2-low/TAM-low, ANGPTL2-low/TAM-high, ANGPTL2-high/TAM-low, and ANGPTL2-high/TAM-high groups. Gene expression datasets of esophageal cancer cell lines were obtained from the cancer cell line encyclopedia public database.

In this study, we demonstrate that TAM infiltration is associated with poor prognosis in patients with esophageal cancer whose tumor cells show relatively higher ANGPTL2 expression levels; however, TAM infiltration did not affect prognosis in patients with ANGPTL2-low-expressing esophageal cancer, suggesting that ANGPTL2 expression in esophageal cancer cells is required for TAM-induced tumor progression. Our analysis of public datasets indicates a potential positive correlation of ANGPTL2 expression levels with that of transforming growth factor (TGF)-β, a TAM-activating factor, in esophageal cancer cell lines.

We conclude that ANGPTL2 signaling in tumor cells supports TAM-induced tumor progression and contributes to poor prognosis in patients with esophageal cancer. These findings overall provide novel insight into pro-tumor ANGPTL2 functions and illustrate the essential role of cancer cell/TAM crosstalk in cancer progression.

The tumor microenvironment (TME) provides essential conditions for the occurrence, invasion, and spread of cancer cells. Initial research has uncovered immunosuppressive properties of the TME, which include low oxygen levels (hypoxia), acidic conditions (low pH), increased interstitial pressure, heightened permeability of tumor vasculature, and an inflammatory microenvironment. The presence of various immunosuppressive components leads to immune evasion and affects immunotherapy efficacy. This indicates the potential value of targeting the TME in cancer immunotherapy. Therefore, TME remodeling has become an effective method for enhancing host immune responses against tumors. In this study, we elaborate on the characteristics and composition of the TME and how it weakens immune surveillance and summarize targeted therapeutic strategies for regulating the TME.

Pancreatic cancer (PC) is a highly aggressive and lethal malignancy characterized by a complex tumor microenvironment (TME) and immunosuppressive features that limit the efficacy of existing treatments. This paper reviews the potential of combining ultrasound with macrophage exhaustion in the treatment of pancreatic cancer. Macrophages, particularly tumor-associated macrophages (TAMs), are crucial in pancreatic cancer progression and immune escape. Prolonged exposure to the immunosuppressive TME leads to macrophage exhaustion, reducing their anti-tumor ability and instead promoting tumor growth. The CSF1/CSF1R signaling pathway is key in macrophage recruitment and functional regulation, making it an effective target for combating macrophage exhaustion. Ultrasound technology not only plays a significant role in diagnosis and staging but also enhances therapeutic efficacy by guiding radiofrequency ablation (RFA) and percutaneous alcohol injection (PEI) in combination with immunomodulators. Additionally, ultrasound imaging can monitor the number and functional status of TAMs in real-time, providing a basis for optimizing treatment strategies. Future studies should further investigate the combined use of ultrasound and immunomodulators to refine treatment regimens, address challenges such as individual variability and long-term effects, and offer new hope for pancreatic cancer patients.

Pruritus, rash, and various other forms of dermatotoxicity are the most frequent adverse events among patients with cancer receiving targeted molecular therapy and immunotherapy. Immune checkpoint inhibitors, macrophage-targeting agents, and epidermal growth factor receptor/MEK inhibitors not only exert antitumor effects but also interfere with molecular pathways essential for skin immune homeostasis. Studying cancer therapy-induced dermatotoxicity helps us identify molecular mechanisms governing skin immunity and deepen our understanding of human biology. This review summarizes new mechanistic insights emerging from the analysis of cutaneous adverse events and discusses knowledge gaps that remain to be closed by future research.

Cholangiocarcinoma (CCA) is a rare but highly invasive cancer, with its incidence rising in recent years. Currently, surgery remains the most definitive therapeutic option for CCA. However, similar to other malignancies, most CCA patients are not eligible for surgical intervention at the time of diagnosis. The chemotherapeutic regimen of gemcitabine combined with cisplatin is the standard treatment for advanced CCA, but its effectiveness is often hampered by therapeutic resistance. Recent research highlights the remarkable plasticity of tumor-associated macrophages (TAMs) within the tumor microenvironment (TME). TAMs play a crucial dual role in either promoting or suppressing tumor development, depending on the factors that polarize them toward pro-tumorigenic or anti-tumorigenic phenotypes, as well as their interactions with cancer cells and other stromal components. In this review, we critically examine recent studies on TAMs in CCA, detailing the expression patterns and prognostic significance of different TAM subtypes in CCA, the mechanisms by which TAMs influence CCA progression and immune evasion, and the potential for reprogramming TAMs to enhance anticancer therapies. This review aims to provide a framework for deeper future research.

Tumor-associated macrophages (TAMs), fundamental constituents of the tumor microenvironment (TME), significantly influence cancer development, primarily by promoting epithelial-mesenchymal transition (EMT). EMT endows cancer cells with increased motility, invasiveness, and resistance to therapies, marking a pivotal juncture in cancer progression. The review begins with a detailed exposition on the origins of TAMs and their functional heterogeneity, providing a foundational understanding of TAM characteristics. Next, it delves into the specific molecular mechanisms through which TAMs induce EMT, including cytokines, chemokines and stromal cross-talking. Following this, the review explores TAM-induced EMT features in select cancer types with notable EMT characteristics, highlighting recent insights and the impact of TAMs on cancer progression. Finally, the review concludes with a discussion of potential therapeutic targets and strategies aimed at mitigating TAM infiltration and disrupting the EMT signaling network, thereby underscoring the potential of emerging treatments to combat TAM-mediated EMT in cancer. This comprehensive analysis reaffirms the necessity for continued exploration into TAMs' regulatory roles within cancer biology to refine therapeutic approaches and improve patient outcomes.

Lung cancer has the highest incidence of brain metastases (BM) among solid organ cancers. Traditionally whole brain radiation therapy has been utilized for non-small-cell lung cancer (NSCLC) BM treatment, although stereotactic radiosurgery has emerged as the superior treatment modality for most patients. Highly penetrant central nervous system (CNS) tyrosine kinase inhibitors have also shown significant CNS activity in patients harboring select oncogenic drivers. There is emerging evidence that patients without oncogene-driven tumors derive benefit from the use of immune checkpoint inhibitors (ICIs). The CNS activity of ICIs have not been well studied given exclusion of patients with active BM from landmark trials, due to concerns of inadequate CNS penetration and activity. However, studies have challenged the idea of an immune-privileged CNS, given the presence of functional lymphatic drainage within the CNS and destruction of the blood brain barrier by BM. An emerging understanding of the interactions between tumor and CNS immune cells in the BM tumor microenvironment also support a role for immunotherapy in BM treatment. In addition, posthoc analyses of major trials have shown improved intracranial response and survival benefit of regimens with ICIs over chemotherapy (CT) alone for patients with BM. Two prospective phase 2 trials evaluating pembrolizumab monotherapy and atezolizumab plus CT in patients with untreated NSCLC BM also demonstrated significant intracranial responses. This review describes the interplay between CNS immune cells and tumor cells, discusses current evidence for ICI CNS activity from retrospective and prospective studies, and speculates on future directions of investigation.

Pancreatic cancer (PC) remains the predominant type of upper gastrointestinal tract cancer, associated with heightened morbidity and a survival rate below 12%. While immunotherapy has brought about transformative changes in the standards of care for most solid tumors, its application in PC is hindered by the ''cold tumor'' microenvironment, marked by the presence of immunosuppressive cells. Modest response rates in PC are attributed, in part to, the fibrotic stroma that obstructs the delivery of systemic immunotherapy. Furthermore, the occurrence of immune-related adverse events (iRAEs) often necessitates the use of sub-therapeutic doses or treatment discontinuation. In the pursuit of innovative approaches to enhance the effectiveness of immunotherapy for PC, implantable drug delivery devices and scaffolds emerge as promising strategies. These technologies offer the potential for sustained drug delivery directly to the tumor site, overcoming stromal barriers, immunosuppression, T cell exclusion, immunotherapy resistance, optimizing drug dosage, and mitigating systemic toxicity. This review offers a comprehensive exploration of pancreatic ductal adenocarcinoma (PDAC), the most common and aggressive form of PC, accompanied by a critical analysis of the challenges the microenvironment presents to the development of successful combinational immunotherapy approaches. Despite efforts, these approaches have thus far fallen short in enhancing treatment outcomes for PDAC. The review will subsequently delve into the imperative need for refining delivery strategies, providing an examination of past and ongoing studies in the field of localized immunotherapy for PDAC. Addressing these issues will lay the groundwork for the development of effective new therapies, thereby enhancing treatment response, patient survival, and overall quality of life for individuals diagnosed with PDAC.

Hepatocellular carcinoma (HCC) is a highly frequent malignancy worldwide. The occurrence and progression of HCC is a complex process closely related to the polarization of tumor-associated macrophages (TAMs) in the tumor microenvironment (TME). The polarization of TAMs is affected by a variety of signaling pathways and surrounding cells. Evidence has shown that TAMs play a crucial role in HCC, through its interaction with other immune cells in the TME. This review summarizes the origin and phenotypic polarization of TAMs, their potential impacts on HCC, and their mechanisms and potential targets for HCC immunotherapy.

Despite the success of immunotherapies for melanoma in recent years, there remains a significant proportion of patients who do not yet derive benefit from available treatments. Immunotherapies currently licensed for clinical use target the adaptive immune system, focussing on Tcell interactions and functions. However, the most prevalent immune cells within the tumor microenvironment (TME) of melanoma are macrophages, a diverse immune cell subset displaying high plasticity, to which no current therapies are yet directly targeted. Macrophages have been shown not only to activate the adaptive immune response, and enhance cancer cell killing, but, when influenced by factors within the TME of melanoma, these cells also promote melanoma tumorigenesis and metastasis.

We present a review of the most up-to-date literatureavailable on PubMed, focussing on studies from within the last 10 years. We also include data from ongoing and recent clinical trials targeting macrophages in melanoma listed on clinicaltrials.gov.

Understanding the multifaceted role of macrophages in melanoma, including their interactions with immune and cancer cells, the influence of current therapies on macrophage phenotype and functions and how macrophages could be targeted with novel treatment approaches, are all critical for improving outcomes for patients with melanoma.

The greatest challenge in cancer therapy is to eradicate cancer cells with minimal damage to normal cells. Targeted therapy has been developed to meet that challenge, showing a substantially increased therapeutic index compared with conventional cancer therapies. Antibodies are important members of the family of targeted therapeutic agents because of their extraordinarily high specificity to the target antigens. Therapeutic antibodies use a range of mechanisms that directly or indirectly kill the cancer cells. Early antibodies were developed to directly antagonize targets on cancer cells. This was followed by advancements in linker technologies that allowed the production of antibody-drug conjugates (ADCs) that guide cytotoxic payloads to the cancer cells. Improvement in our understanding of the biology of T cells led to the production of immune checkpoint-inhibiting antibodies that indirectly kill the cancer cells through activation of the T cells. Even more recently, bispecific antibodies were synthetically designed to redirect the T cells of a patient to kill the cancer cells. In this Review, we summarize the different approaches used by therapeutic antibodies to target cancer cells. We discuss their mechanisms of action, the structural basis for target specificity, clinical applications and the ongoing research to improve efficacy and reduce toxicity.

Solid tumors are the most prevalent form of cancer. Considerable technological and medical advancements had been achieved for the diagnosis of the disease. However, detection of the disease in an early stage is of utmost importance, still far from reality. On the contrary, the treatment and therapeutic area to combat solid tumors are still in its infancy. Conventional treatments like chemotherapy and radiation therapy pose challenges due to their indiscriminate impact on healthy and cancerous cells. Contextually, efficient drug targeting is a pivotal approach in solid tumor treatment. This involves the precise delivery of drugs to cancer cells while minimizing harm to healthy cells. Targeted drugs exhibit superior efficacy in eradicating cancer cells while impeding tumor growth and mitigate side effects by optimizing absorption which further diminishes the risk of resistance. Furthermore, tailoring targeted therapies to a patient's tumor-specific molecular profile augments treatment efficacy and reduces the likelihood of relapse. This chapter discuss about the distinctive characteristics of solid tumors, the possibility of early detection of the disease and potential therapeutic angle beyond the conventional approaches. Additionally, the chapter delves into a hitherto unknown attribute of magnetic field effect to target cancer cells which exploit the relatively less susceptibility of normal cells compared to cancer cells to magnetic fields, suggesting a future potential of magnetic nanoparticles for selective cancer cell destruction. Lastly, bioinformatics tools and other unconventional methodologies such as AI-assisted codon bias analysis have a crucial role in comprehending tumor biology, aiding in the identification of futuristic targeted therapies.

Currently, antitumor drugs show limited clinical outcomes, mainly due to adaptive resistance. Clinical evidence has highlighted the importance of the tumor microenvironment (TME) and tumor-associated macrophages (TAMs) in tumor response to conventional antitumor drugs. Preclinical studies show that TAMs following antitumor agent can be reprogrammed to an immunosuppressive phenotype and proangiogenic activities through different mechanisms, mediating drug resistance and poor prognosis. Potential extrinsic inhibitors targeting TAMs repolarize to an M1-like phenotype or downregulate proangiogenic function, enhancing therapeutic efficacy of anti-tumor therapy. Moreover, pharmacological modulation of macrophages that restore the immune stimulatory characteristics is useful to reshaping the tumor microenvironment, thus further limiting tumor growth. This review aims to introduce macrophage response in tumor therapy and provide a potential therapeutic combination strategy of TAM-targeting immunomodulation with conventional antitumor drugs.

Cancer remains a significant challenge for public healthcare systems worldwide. Within the realm of cancer treatment, considerable attention is focused on understanding the tumor microenvironment (TME)-the complex network of non-cancerous elements surrounding the tumor. Among the cells in TME, tumor-associated macrophages (TAMs) play a central role, traditionally categorized as pro-inflammatory M1 macrophages or anti-inflammatory M2 macrophages. Within the TME, M2-like TAMs can create a protective environment conducive to tumor growth and progression. These TAMs secrete a range of factors and molecules that facilitate tumor angiogenesis, increased vascular permeability, chemoresistance, and metastasis. In response to this challenge, efforts are underway to develop adjuvant therapy options aimed at reprogramming TAMs from the M2 to the anti-tumor M1 phenotype. Such reprogramming holds promise for suppressing tumor growth, alleviating chemoresistance, and impeding metastasis. Nanotechnology has enabled the development of nanoformulations that may soon offer healthcare providers the tools to achieve targeted drug delivery, controlled drug release within the TME for TAM reprogramming and reduce drug-related adverse events. In this review, we have synthesized the latest data on TAM polarization in response to TME factors, highlighted the pathological effects of TAMs, and provided insights into existing nanotechnologies aimed at TAM reprogramming and depletion.

As one of the most common malignant tumors in the world, lung cancer has limited benefits for patients despite its diverse treatment methods due to factors such as personalized medicine targeting histological type, immune checkpoint expression, and driver gene mutations. The high mortality rate of lung cancer is partly due to the immune-suppressive which limits the effectiveness of anti-cancer drugs and induces tumor cell resistance. The currently widely recognized TAM phenotypes include the anti-tumor M1 and pro-tumor M2 phenotypes. M2 macrophages promote the formation of an immune-suppressive microenvironment and hinder immune cell infiltration, thereby inhibiting activation of the anti-tumor immune system and aiding tumor cells in resisting treatment. Analyzing the relationship between different treatment methods and macrophages in the TME can help us better understand the impact of TAMs on lung cancer and confirm the feasibility of targeted TAM therapy. Targeting TAMs to reduce the M2/M1 ratio and reverse the immune-suppressive microenvironment can improve the clinical efficacy of conventional treatment methods and potentially open up more efficient combination treatment strategies, maximizing the benefit for lung cancer patients.

Gastric cancer (GC) is a malignant tumor that originates from the epithelium of the gastric mucosa. The latest global cancer statistics show that GC ranks fifth in incidence and fourth in mortality among all cancers, posing a serious threat to public health. While early-stage GC is primarily treated through surgery, chemotherapy is the frontline option for advanced cases. Currently, commonly used chemotherapy regimens include FOLFOX (oxaliplatin + leucovorin + 5-fluorouracil) and XELOX (oxaliplatin + capecitabine). However, with the widespread use of chemotherapy, an increasing number of cases of drug resistance have emerged. This article primarily explores the potential mechanisms of chemotherapy resistance in GC patients from five perspectives: cell death, tumor microenvironment, non-coding RNA, epigenetics, and epithelial-mesenchymal transition. Additionally, it proposes feasibility strategies to overcome drug resistance from four angles: cancer stem cells, tumor microenvironment, natural products, and combined therapy. The hope is that this article will provide guidance for researchers in the field and bring hope to more GC patients.

Macrophages are the main component of the tumor microenvironment, which are differentiated from monocytes in the blood and play an important role in cancer development. Tumor-associated macrophages (TAMs) can promote tumor growth, invasion, metastasis, and resistance to anti-programmed death receptor 1 therapy by regulating programmed cell death ligand 1 expression and interacting with other immune cells in the tumor microenvironment. However, when activated properly, macrophages can also play an anti-tumor role by enhancing the phagocytosis and cytotoxicity of tumor cells. TAM is associated with poor prognosis and drug resistance in patients treated with immunotherapy, indicating that macrophages are attractive targets for combined therapy in cancer treatment. Combination of targeting TAMs and immunotherapy overcomes the drug resistance and achieved excellent results in some cancers, which may be a promising strategy for cancer treatment in the future. Herein, we review the recent findings on the role of macrophages in tumor development, metastasis, and immunotherapy. We focus mainly on macrophage≥centered therapy, including strategies to deplete and reprogram TAMs, which represent the potential targets for improving tumor immunotherapy efficacy.