Adjuvant platinum-based chemotherapy for completely resected non-small cell lung cancer is associated with modest improvement in survival; nevertheless, no validated biomarker exists for predicting the benefit or harm of adjuvant platinum-based chemotherapy.

We simultaneously measured 27 cytokines in operative tumor specimens from a discovery cohort (n = 97) by multiplex immunoassay; half of the patients received adjuvant platinum-based chemotherapy, and the other half were observed. We tested possible prognostic and predictive factors in multivariate Cox models for overall survival (OS) and relapse-free survival (RFS), and a tree-based method was applied to detect predictive factors with respect to RFS. The results were validated in an independent validation cohort (n = 93).

Fifty-two of 97 (54 %) patients in the discovery cohort and 50 of 93 (54 %) in the validation cohort received adjuvant chemotherapy; forty-four (85 %) patients in the discovery cohort and 37 (74 %) in the validation cohort received four cycles as planned. In patients with low IL-1β-expressing tumors, RFS and OS were worse after adjuvant chemotherapy than after observation. The limited effect of adjuvant chemotherapy for patients with low IL-1β-expressing tumors was confirmed in the validation cohort. Additionally, RFS and OS were prolonged by adjuvant chemotherapy only in patients with high IL-1β-expressing tumors in the validation cohort.

This study identified and validated low tumor IL-1β expression as a potential biomarker of a limited response to adjuvant platinum-based chemotherapy after complete resection of pulmonary adenocarcinoma. This finding has the potential to inform adjuvant treatment decisions.

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.

The initiation of tumor-specific T cell responses is critically dependent on antigen-presenting cells (APCs). Nevertheless, as the most dominant APCs in tumors, M2-like macrophages largely restrained T cell activation due to inefficient antigen cross-presentation. Herein, we rationally designed a nano-immunomodulator (FANP) to restore the antigen presentation capability of M2-like macrophages by amplifying stimulator of interferon genes (STING) activation. FANPs were fabricated by self-assembly of Fe3+ and Raddeanin A (RA), which rapidly degraded when reaching tumor microenvironment. The released Fe3+ induced the polarization of M2-like macrophages into M1 phenotype, followed by RA stimulation for amplified STING activation, allowing robust antigen cross-presentation and T cell-driven anti-tumor response, leading to effective tumor regression in both immunogenic and poor-immunogenic tumor models. Notably, FANPs exhibited intensive STING activation in human tumor samples, showing potential for clinical impact. Our work offers a simple and robust strategy to re-educate M2-like macrophages by augmenting STING activation for cancer immunotherapy.

How tumor microenvironment shapes lung adenocarcinoma (LUAD) precancer evolution remains poorly understood. Spatial immune profiling of 114 human LUAD and LUAD precursors reveals a progressive increase of adaptive response and a relative decrease of innate immune response as LUAD precursors progress. The immune evasion features align the immune response patterns at various stages. TIM-3-high features are enriched in LUAD precancers, which decrease in later stages. Furthermore, single-cell RNA sequencing (scRNA-seq) and spatial immune and transcriptomics profiling of LUAD and LUAD precursor specimens from 5 mouse models validate high TIM-3 features in LUAD precancers. In vivo TIM-3 blockade at precancer stage, but not at advanced cancer stage, decreases tumor burden. Anti-TIM-3 treatment is associated with enhanced antigen presentation, T cell activation, and increased M1/M2 macrophage ratio. These results highlight the coordination of innate and adaptive immune response/evasion during LUAD precancer evolution and suggest TIM-3 as a potential target for LUAD precancer interception.

Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality worldwide. Conventional therapies are frequently limited by tumor heterogeneity and the immunosuppressive tumor microenvironment (TME). Dendritic cells (DCs), central to orchestrating antitumor immunity, have become key targets for HCC immunotherapy. This review examines the biological functions of DC subsets (cDC1, cDC2, pDC, and moDC) and their roles in initiating and modulating immune responses against HCC. We detail the mechanisms underlying DC impairment within the TME, including suppression by regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and cancer-associated fibroblasts (CAFs). Additionally, we discuss novel DC-based therapeutic strategies, such as DC-based vaccines designed to enhance antigen presentation and T cell activation. Combining DC vaccines with immune checkpoint inhibitors (ICIs), including PD-1/PD-L1 and CTLA-4 blockers, demonstrates synergistic effects that can overcome immune evasion and improve clinical outcomes. Despite progress, challenges related to DC subset heterogeneity, TME complexity, and patient variability require the further optimization and personalization of DC-based therapies. Future research should focus on refining these strategies, leveraging advanced technologies like genomic profiling and artificial intelligence, to maximize therapeutic efficacy and revolutionize HCC treatment. By restoring DC function and reprogramming the TME, DC-based immunotherapy holds immense potential to transform the management of HCC and improve patient survival.

A T cell-inflamed tumor microenvironment is predictive of better prognosis and clinical response to immunotherapy. Proteinase-activated receptor 2 (PAR2), a member of G-protein coupled receptors is involved in inflammatory process and the progression of various cancers. However, the role of PAR2 in modulating the tumor microenvironment remains unclear. Here, we found that PAR2 high-expression was associated with a favorable prognosis in patients with colorectal cancer. Intriguingly, PAR2 expression in human colorectal cancer was mainly confined to tumor cells and was significantly associated with CD8+ T cell infiltration. Tumor-intrinsic PAR2 deficiency blunted antitumor immune responses to promote tumor growth and attenuated the therapeutic efficacy of anti-PD1 in a mouse model of colon cancer. Tumors with downregulated PAR2 showed decreased CD8+ T cell infiltration and impaired effector function. Mechanistically, PAR2 activation in tumor cells induced CXCL9 and CXCL10 production via PI3K/AKT/mTOR signaling, thereby enhancing CD8+ T cell recruitment in the tumor microenvironment. In addition, PAR2 was essential for dendritic cell activation and differentiation towards conventional type 1 subset. PAR2 deficiency in dendritic cells markedly impaired their ability to prime CD8+ T cells and control tumor growth in vivo. Thus, our findings identify new roles for PAR2 in promoting antitumor immunity and provide a promising target to improve immunotherapy efficacy in colorectal cancer.

Dendritic cells (DCs) constitute a distinct type of immune cell found within tumors, serving a central role in mediating tumor antigen-specific immunity against cancer cells. Frequently, DC functions are dysregulated by the immunosuppressive signals present within the tumor microenvironment (TME). Consequently, DC manipulation holds great potential to enhance the cytotoxic T cell response against cancer diseases. One strategy involves administering Fms-like tyrosine kinase receptor 3 ligand (Flt3L), a vitally important cytokine for DC development. In this current study, the electroporation-mediated delivery of a novel albumin-fused Flt3L DNA (alb-Flt3L DNA) demonstrated the ability to induce an anti-tumor immune response. This albumin fusion construct possesses more persistent bioactivity in targeted organs. Furthermore, TC-1-bearing-C57BL/6 mice receiving alb-Flt3L DNA treatment presented better tumor control and superior survival. Cellular analysis revealed that alb-Flt3L DNA administration promoted robust DC and cDC1 expansion. In addition, increased levels of IFN-γ-secreting CD8+ lymphocytes were found in correlation to greater cDC1 population. Moreover, the toxicity of alb-Flt3L administration is limited. Collectively, our data showcases a novel DC-based immunotherapy using electroporation to administer alb-Flt3L DNA.

Macrophage-based cancer cellular therapy has gained substantial interest. However, the capability of engineered macrophages to target cancer heterogeneity and modulate adaptive immunity remains unclear. Here, exploiting the myeloid antibody-dependent cellular phagocytosis biology and phagocytosis checkpoint blockade, we report the enhanced synthetic phagocytosis receptor (eSPR) that integrate FcRγ-driven phagocytic chimeric antigen receptors (CAR) with built-in secreted CD47 blockers. The eSPR engineering empowers macrophages to combat tumor antigen heterogeneity. Transduced by adenoviral vectors, eSPR macrophages are intrinsically pro-inflammatory imprinted and resist tumoral polarization. Transcriptomically and phenotypically, eSPR macrophages elicit a more favorable tumor immune landscape. Mechanistically, eSPR macrophages in situ stimulate CD8 T cells via phagocytosis-dependent antigen cross-presentation. We also validate the functionality of the eSPR system in human primary macrophages.

Patients with peritoneal metastasized colorectal cancer (PM-CRC) have a dismal prognosis. We hypothesized that an immunosuppressive environment in the peritoneal cavity underlies poor prognosis. We define the composition of the human peritoneal immune system (PerIS) using single-cell technologies in 18 patients with- and without PM-CRC, as well as in matched peritoneal metastases (n = 8). Here we show that the PerIS contains abundant immunosuppressive C1Q+VSIG4+ and SPP1+VSIG4+ peritoneal-resident macrophages (PRMs), as well as monocyte-like cavity macrophages (mono-CMs), which share features with tumor-associated macrophages, even in homeostasis. In PM-CRC, expression of immunosuppressive cytokines IL10 and VEGF increases, while simultaneously expression of antigen-presenting molecules decreases in PRMs. These intratumoral suppressive PRMs originate from the PerIS, and intraperitoneal depletion of PRMs in vivo using anti-CSF1R combined with anti-PD1 significantly reduces tumor burden and improves survival. Thus, PRMs define a metastatic site-specific immunosuppressive niche, and targeting PRMs is a promising treatment strategy for PM-CRC.

Cytotoxic T cell immune responses against cancer crucially depend on the ability of a subtype of professional antigen-presenting cells termed conventional type 1 dendritic cells (cDC1s) to cross-present antigens. Cross-presentation comprises redirection of exogenous antigens taken from other cells to the major histocompatibility complex class I antigen-presenting machinery. In addition, once activated and having sensed viral moieties or T helper cell cooperation via CD40-CD40L interactions, cDC1s provide key co-stimulatory ligands and cytokines to mount and sustain CD8+ T cell immune responses. This regulated process of cognate T cell activation is termed cross-priming. In cancer mouse models, CD8+ T cell cross-priming by cDC1s is crucial for the efficacy of most, if not all, immunotherapy strategies. In patients with cancer, the presence and abundance of cDC1s in the tumour microenvironment is markedly associated with the level of T cell infiltration and responsiveness to immune checkpoint inhibitors. Therapeutic strategies to increase the numbers of cDC1s using FMS-like tyrosine kinase 3 ligand (FLT3L) and/or their activation status show evidence of efficacy in cancer mouse models and are currently being tested in initial clinical trials with promising results so far.

Immune checkpoint therapeutics including CD40 agonists have tremendous promise to elicit antitumor responses in patients resistant to current therapies. Conventional immune checkpoint inhibitors (PD-1, PD-L1 and CTLA-4 antagonists) are associated with serious adverse cardiac events including life-threatening myocarditis. However, little is known regarding the potential for CD40 agonists to trigger myocardial inflammation or myocarditis. Here we leverage genetic mouse models, single-cell sequencing and cell depletion studies to show that an anti-CD40 agonist antibody reshapes the cardiac immune landscape through activation of CCR2+ macrophages and subsequent recruitment of effector memory CD8+ T cells. We identify a positive feedback loop between CCR2+ macrophages (positive for the chemokine receptor CCR2) and CD8+ T cells driven by IL-12b, TNF and IFNγ signaling that promotes myocardial inflammation and show that previous exposure to CD40 agonists sensitizes the heart to secondary insults and accelerates left ventricular remodeling. Collectively, these findings highlight the potential for CD40 agonists to promote myocardial inflammation and potentiate heart failure pathogenesis.

Cancer is the result of evolving crosstalk between neoplastic cell and its immune microenvironment. In recent years, immune therapeutics targeting T lymphocytes, such as immune checkpoint blockade (ICB) and CAR-T, have made significant progress in cancer treatment and validated targeting immune cells as a promising approach to fight human cancers. However, responsiveness to the current immune therapeutic agents is limited to only a small proportion of solid cancer patients. As major components of most solid tumors, myeloid cells played critical roles in regulating the initiation and sustentation of adaptive immunity, thus determining tumor progression as well as therapeutic responses. In this review, we discuss emerging data on the diverse functions of myeloid cells in tumor progression through their direct effects or interactions with other immune cells. We explain how different metabolic reprogramming impacts the characteristics and functions of tumor myeloid cells, and discuss recent progress in revealing different mechanisms-chemotaxis, proliferation, survival, and alternative sources-involved in the infiltration and accumulation of myeloid cells within tumors. Further understanding of the function and regulation of myeloid cells is important for the development of novel strategies for therapeutic exploitation in cancer.

The tumor microenvironment is a dynamic and complex three-dimensional network comprising the extracellular matrix and diverse non-cancerous cells, including fibroblasts, adipocytes, endothelial cells and various immune cells (lymphocytes T and B, NK cells, dendritic cells, monocytes/macrophages, myeloid-derived suppressor cells, and innate lymphoid cells). A constantly and rapidly growing number of studies highlight the critical role of these cells in shaping cancer survival, metastatic potential and therapy resistance. This review provides a synthesis of current knowledge on the modulating role of the cellular microenvironment in cancer progression and response to treatment.

Taxanes are effective in several solid tumors. Paclitaxel, the main clinically available taxane, was approved in the early nineties, for the treatment of ovarian cancer and later on, together with the analogs docetaxel and cabazitaxel, for other malignancies. By interfering with microtubule function and impairing the separation of sister cells at mitosis, taxanes act as antimitotic agents, thereby counteracting the high proliferation rate of cancer cells. The action of taxanes goes beyond their antimitotic function because their main cellular targets, the microtubules, participate in multiple processes such as intracellular transport and cell shape maintenance. The clinical efficacy of taxanes is limited by the development of multiple resistance mechanisms. Among these, extracellular vesicles have emerged as new players. In addition, taxane metronomic schedules shows an impact on the tumor microenvironment reflected by antiangiogenic and immunomodulatory effects, an aspect of growing interest considering their inclusion in treatment regimens with immunotherapeutics. Preclinical studies have paved the bases for synergistic combinations of taxanes both with conventional and targeted agents. A variety of drug delivery strategies have provided novel opportunities to increase the drug activity. The ability of taxanes to orchestrate different cellular effects amenable to modulation suggests novel options to improve cures in lethal malignancies.

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.

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.

Breast cancer (BC) is the most common cancer in women and a leading cause of cancer-related mortality. Despite advances in screening and treatment, outcomes for advanced or recurrent BC remain poor, highlighting the need for new strategies. Recent research emphasizes the tumor microenvironment (TME), particularly tumor-associated macrophages (TAMs), as key drivers of tumor growth, metastasis, and resistance to therapy. The presence of M2-like TAMs in the TME promotes immune evasion and tumor progression across BC subtypes. This review summarizes TAMs classification, their role in BC, and emerging therapies targeting TAMs, including depletion, inhibition of recruitment, and reprogramming from pro-tumoral M2 to anti-tumoral M1 phenotypes. Targeting TAMs offers a promising strategy to improve BC treatment outcomes.

Various components of the immunological milieu surrounding tumors have become a key focus in cancer immunotherapy research. There are currently no reliable biomarkers for triple-negative breast cancer (TNBC), leading to limited clinical benefits. However, some studies have indicated that patients with TNBC may achieve better outcomes after immunotherapy. Therefore, this study aimed to identify molecular features potentially associated with conventional type 1 dendritic cell (cDC1) immunity to provide new insights into TNBC prognostication and immunotherapy decision-making.

Single-cell ribonucleic acid sequencing data from the Gene Expression Omnibus database were analyzed to determine which genes are differentially expressed genes (DEGs) in cDC1s. We then cross-referenced cDC1-related DEGs with gene sets linked to immunity from the ImmPort and InnateDB databases to screen for the genes linked to the immune response and cDC1s. We used univariate Cox and least absolute shrinkage and selection operator regression analyses to construct a risk assessment model based on four genes in patients with TNBC obtained from the Cancer Genome Atlas, which was validated in a testing group. This model was also used to assess immunotherapy responses among the IMvigor210 cohort. We subsequently utilized single sample Gene Set Enrichment Analysis, CIBERSORT, and ESTIMATE to analyze the immunological characteristics of the feature genes and their correlation with drug response.

We identified 93 DEGs related to the immune response and cDC1s, of which four (IDO1, HLA-DOB, CTSD, and IL3RA) were substantially linked to the overall survival rate of TNBC patients. The risk assessment model based on these genes stratified patients into high- and low-risk groups. Low-risk patients exhibited enriched ''hot tumor'' phenotypes, including higher infiltration of memory-activated CD4 + T cells, CD8 + T cells, gamma delta T cells, and M1 macrophages, as well as elevated immune checkpoint expression and tumor mutational burden, suggesting potential responsiveness to immunotherapy. Conversely, high-risk patients displayed "cold tumor" characteristics, with higher infiltration of M0 and M2 macrophages and lower immune scores, which may be poorer in response to immunotherapy. However, experimental validation and larger clinical studies are necessary to confirm these findings and explore the underlying mechanisms of the identified genes.

This study developed a robust risk assessment model using four genes that effectively forecast the outcome of patients with TNBC and have the potential to guide immunotherapy. This model provided new theoretical insights for knowing the TNBC immune microenvironment and developing personalized treatment strategies.

Cancer continues to be a major global health burden, with high morbidity and mortality. Building on the success of immune checkpoint inhibitors and adoptive cellular therapy, cancer vaccines have garnered significant interest, but their clinical success remains modest. Benefiting from advancements in technology, many meticulously designed cancer vaccines have shown promise, warranting further investigations to reach their full potential. Cancer vaccines hold unique benefits, particularly for patients resistant to other therapies, and they offer the ability to initiate broad and durable T cell responses. In this review, we highlight the antigen selection for cancer vaccines, introduce the immune responses induced by vaccines, and propose strategies to enhance vaccine immunogenicity. Furthermore, we summarize key features and notable clinical advances of various vaccine platforms. Lastly, we delve into the mechanisms of tumor resistance and explore the potential benefits of combining cancer vaccines with standard treatments and other immunomodulatory approaches to improve vaccine efficacy.

Tyrosine kinase inhibitors (TKIs) have transformed the treatment of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer. However, treatment resistance remains a major challenge in clinical practice. The tumor microenvironment (TME) is a complex system composed of tumor cells, immune and non-immune cells, and non-cellular components. Evidence indicates that dynamic changes in TME during TKI treatment are associated with the development of resistance. Research has focused on identifying how each component of the TME interacts with tumors and TKIs to understand therapeutic targets that could address TKI resistance. In this review, we describe how TME components, such as immune cells, fibroblasts, blood vessels, immune checkpoint proteins, and cytokines, interact with EGFR-mutant tumors and how they can promote resistance to TKIs. Furthermore, we discuss potential strategies targeting TME as a novel therapeutic approach.

In situ vaccination is considered a promising cancer immunotherapy strategy to elicit a tumor-specific T cell response. Live bacteria effectively enhanced the immune response in irradiated tumors as it can activate multiple immune cells. However, the adaptive immune response remains low since bacteria lack the efficient delivery of antigen to dendritic cells (DCs). Here, we show that tumor antigens can be metabolically labeled with azido groups in situ, allowing for their specific capture by orthogonally engineered Salmonella via bioorthogonal chemistry. Subsequently, these antigens are efficiently delivered to DCs through the active movement of the bacteria. Intratumorally injected engineered bacteria captured the labeled antigens and improved their presentation by DCs. This increased the proportion of antigen-specific CD8+ T cells in tumors, further resulting in systemic antitumor effects in the bilateral melanoma mouse model. The antitumor effects were abrogated in Batf3-/- mice or after CD8+ T cell depletion, indicating that systemic antitumor effects were dependent on adaptive immune responses. Overall, our work presents a strategy combining bacterial engineering and antigen labeling, which may guide the development of in situ vaccines in the future.

Macrophages are present at high frequency in most solid tumor types, and their relative abundance negatively correlates with therapy responses and survival outcomes. Tissue-resident macrophages are highly tuned to integrate tissue niche signals, and multiple factors within the idiosyncratic tumor microenvironment (TME) drive macrophages to polarization states that favor immune suppression, tumor growth and metastasis. These diverse functional states are underpinned by extensive and complex rewiring of tumor-associated macrophage (TAM) metabolism. In this Review, we link distinct and specific macrophage functional states within the TME to major, phenotype-sustaining metabolic programs and discuss the metabolic impact of macrophage-modulating therapeutic interventions.

The cytokine interleukin-10 (IL-10) limits the immune response and promotes resolution of acute inflammation. Because of its immunosuppressive effects, IL-10 up-regulation is a common feature of tumor progression and metastasis. Recently, IL-10 regulation has been shown to depend on mitochondria and redox-sensitive signals. We have found that Suppressor of site IIIQo Electron Leak 1.2 (S3QEL 1.2), a specific inhibitor of reactive oxygen species (ROS) production from mitochondrial complex III, and myxothiazol, a complex III inhibitor, decrease IL-10 in lipopolysaccharide (LPS)-activated macrophages. IL-10 down-regulation is likely to be mediated by suppression of c-Fos, which is a subunit of activator protein 1 (AP1), a transcription factor required for IL-10 gene expression. S3QEL 1.2 impairs IL-10 production in vivo after LPS challenge and promotes the survival of mice bearing B16F10 melanoma by lowering tumor growth. Our data identify a link between complex III-dependent ROS generation and IL-10 production in macrophages, the targeting of which could have potential in boosting antitumor immunity.

Tumour-associated macrophages (TAMs) are crucial in the progression and treatment response of oral squamous cell carcinoma (OSCC). TAMs infiltrate OSCC, adopting an M2-like phenotype that promotes tumour growth, metastasis and immune suppression. The current narrative review explored the roles of TAMs in OSCC, focusing on their impact on the tumour microenvironment, invasion, metastasis, angiogenesis, immunosuppression and potential therapeutic targeting.

A comprehensive analysis of the current literature on TAMs in OSCC was conducted. Specifically, we evaluated the biological functions of TAMs, their interactions within the tumour microenvironment, and their influence on disease progression and treatment outcomes.

TAMs contribute to OSCC progression by secreting cytokines, such as IL-10 and TGF-β, that inhibit effector immune cells. They facilitate angiogenesis, extracellular matrix remodelling and the epithelial-mesenchymal transition, which are essential for tumour invasion and metastasis. TAMs support cancer stem cells and recruit regulatory T cells and myeloid-derived suppressor cells, enhancing resistance to therapies. Their presence correlates with advanced OSCC stages, lymph node metastasis and poor prognosis.

TAMs regulate OSCC progression and therapy resistance. Reprogramming them to an M1-like phenotype or depleting them enhances treatments. Understanding TAM-OSCC interactions is crucial for developing interventions against their tumour-promoting functions and restoring anti-tumour immunity.

Immune responses against cancer are dominated by T cell exhaustion and dysfunction. Recent advances have underscored the critical role of early priming interactions in establishing T cell fates. In this review, we explore the importance of dendritic cell (DC) signals in specifying CD8+ T cell fates in cancer, drawing on insights from acute and chronic viral infection models. We highlight the role of DCs in lymph nodes and tumors in maintaining stem-like CD8+ T cells, which are critical for durable antitumor immune responses. Understanding how CD8+ T cell fates are determined will enable the rational design of immunotherapies, particularly therapeutic cancer vaccines, that can modulate DC-T cell interactions to generate beneficial CD8+ T cell fates.

CD206 is a common marker of a putative immunosuppressive "M2" state in tumor-associated macrophages (TAMs). We made a novel conditional CD206 (Mrc1) knock-in mouse to specifically visualize and/or deplete CD206+ TAMs. Early depletion of CD206+ macrophages and monocytes (Mono/Macs) led to the indirect loss of conventional type I dendritic cells (cDC1), CD8 T cells, and NK cells in tumors. CD206+ TAMs robustly expressed CXCL9, contrasting with stress-responsive Spp1-expressing TAMs and immature monocytes, which became prominent with early depletion. CD206+ TAMs differentially attracted activated CD8 T cells, and the NK and CD8 T cells in CD206-depleted tumors were deficient in Cxcr3 and cDC1-supportive Xcl1 and Flt3l expressions. Disrupting this key antitumor axis decreased tumor control by antigen-specific T cells in mice. In human cancers, a CD206Replete, but not a CD206Depleted Mono/Mac gene signature correlated robustly with CD8 T cell, cDC1, and NK signatures and was associated with better survival. These findings negate the unqualified classification of CD206+ "M2-like" macrophages as immunosuppressive.

The role of tumor-associated macrophages (TAMs) in cervical cancer (CC) remains controversial. Here, we report a meta-analysis of the association between TAMs infiltration and clinical outcomes.

PubMed, Embase, Web of Science, and CNKI were searched systematically from inception until December 20, 2023. Studies involving TAMs and prognosis, clinical, or pathological features were included. Quality assessments of the selected studies were assessed. The fixed-effect or random-effects model, standard mean difference (SMD), odds ratios (OR), or hazard ratios (HR) with 95% confidence intervals (CIs) were used as the effect size estimate.

26 eligible studies with 2,295 patients were identified. Our meta-analysis revealed that TAMs were overexpressed in CC (OR = 12.93, 95% CI = 7.73-21.61 and SMD = 1.58, 95% CI = 0.95-2.21) and that elevated TAM levels were strongly associated with lymph node metastasis (LNM) (SMD = 0.51, 95% CI = 0.90-2.01) and FIGO stages (SMD = 0.46, 95% CI = 0.08-0.85). Subgroup analysis indicated a significant positive correlation between LNM and TAMs density in tumor stroma, but not in cancer nests (SMD = 0.58, 95% CI = 0.31-0.58). Furthermore, in early stage, a stronger correlation exists between LNM and TAM density (SMD = 1.21, 95% CI = 0.75-1.66). In addition, it revealed that patients with high TAMs expression had poorer overall survival (OS) (HR = 2.55 95% CI = 1.59-4.07) and recurrence-free survival (RFS) (HR = 2.17, 95% CI = 1.40-3.35).

Our analyses suggest that a high density of TAMs predicts adverse outcomes in CC.

Ductal carcinoma in situ (DCIS) accounts for ~20% of all breast cancer diagnoses but whilst known to be a precursor of invasive breast cancer (IBC), evidence suggests only one in six patients will ever progress. A key challenge is to distinguish between those lesions that will progress and those that will remain indolent. Molecular analyses of neoplastic epithelial cells have not identified consistent differences between lesions that progressed and those that did not, and this has focused attention on the tumour microenvironment (ME).The DCIS ME is unique, complex and dynamic. Myoepithelial cells form the wall of the ductal-lobular tree and exhibit broad tumour suppressor functions. However, in DCIS they acquire phenotypic changes that bestow them with tumour promoter properties, an important evolution since they act as the primary barrier for invasion. Changes in the peri-ductal stromal environment also arise in DCIS, including transformation of fibroblasts into cancer-associated fibroblasts (CAFs). CAFs orchestrate other changes in the stroma, including the physical structure of the extracellular matrix (ECM) through altered protein synthesis, as well as release of a plethora of factors including proteases, cytokines and chemokines that remodel the ECM. CAFs can also modulate the immune ME as well as impact on tumour cell signalling pathways. The heterogeneity of CAFs, including recognition of anti-tumourigenic populations, is becoming evident, as well as heterogeneity of immune cells and the interplay between these and the adipocyte and vascular compartments. Knowledge of the impact of these changes is more advanced in IBC but evidence is starting to accumulate for a role in DCIS. Detailed in vitro, in vivo and tissue studies focusing on the interplay between DCIS epithelial cells and the ME should help to define features that can better predict DCIS behaviour.

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

Macrophages are pivotal in driving breast tumor development, progression, and resistance to treatment, particularly in estrogen receptor-positive (ER+) tumors, where they infiltrate the tumor microenvironment (TME) influenced by cancer cell-secreted factors. By analyzing single-cell RNA sequencing data from 25 ER+ tumors, we elucidated interactions between cancer cells and macrophages, correlating macrophage density with epithelial cancer cell density. We identified that S100A11, a previously unexplored factor in macrophage-cancer crosstalk, predicts high macrophage density and poor outcomes in ER+ tumors. We found that recombinant S100A11 enhances macrophage infiltration and migration in a dose-dependent manner. Additionally, in a 3D matrix using a panel of three ER+ breast cancer cell lines, we showed that secreted S100A11 levels from cancer cells were associated with increased monocyte infiltration that subsequently differentiation toward macrophages. Genetic silencing of S100A11 in the S100A11-high T47D cancer cells reduced monocyte infiltration, consistent with results using a S100A11 blocking antibody in T47D cancer cells and in a clinically relevant patient-derived organoid model. Phenotypic analysis of macrophages cocultured with T47D cancer cells following S100A11 knockdown revealed lower expression of the immunosuppressive marker CD206, further underscoring the role of S100A11 as a paracrine regulator of pro-tumorigenic cancer-macrophage crosstalk. This study offers novel insights into the interplay between macrophages and cancer cells in ER+ breast tumors, highlighting S100A11 as a potential therapeutic target to modulate the macrophage-rich tumor microenvironment.

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

Triple-Negative Breast Cancer (TNBC), the most challenging subtype of Breast Cancer (BC), currently lacks targeted therapy, presenting a significant therapeutic gap in its management. Tumor Associated Macrophages (TAMs) play a significant role in TNBC progression and could be targeted by repolarizing them from M2 to M1 phenotype. Matairesinol (MAT), a plant lignan, has been shown to exhibit anticancer, anti-inflammatory and immunomodulatory activities. In this study, we explored how MAT-induced repolarization of THP-1-derived M2 macrophages towards the M1 phenotype, which could effectively target the TNBC cell line, MDA-MB-231.

The differential expression of genes in THP-1-derived macrophages at mRNA levels was evaluated by RNAseq assay. An inverted microscope equipped with a CMOS camera was utilized to capture the morphological variations in THP-1 cells and THP-1-derived macrophages. Relative mRNA expression of M1 and M2 specific marker genes was quantified by qRT-PCR. Cell viability and induction of apoptosis were evaluated by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) and 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolylcarbocyanine iodide (JC-1 dye) assays, respectively.

MAT reduced the viability of M2a and M2d macrophages and repolarized them to M1 phenotype. Conditioned medium (CM) from MAT-treated M2a and M2d macrophages significantly reduced the viability of TNBC cells by apoptosis.

Targeting M2 macrophages is an important strategy to regulate cancer progression. Our study provides evidence that MAT may be a promising drug candidate for developing novel anti-TNBC therapy. However, further studies are warranted to thoroughly elucidate the molecular mechanism of action of MAT and evaluate its therapeutic potential in TNBC in vitro and in vivo models.