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Chimeric antigen receptor macrophage (CAR-MΦ) represents a significant advancement in immunotherapy, especially for treating solid tumors where traditional CAR-T therapies face limitations. CAR-MΦ offers a promising approach to target and eradicate tumor cells by utilizing macrophages phagocytic and antigen-presenting abilities. However, challenges such as the complex tumor microenvironment (TME), variability in antigen expression, and immune suppression limit their efficacy. This review addresses these issues, exploring mechanisms of CAR-MΦ action, optimal construct designs, and interactions within the TME. It also delves into the ex vivo manufacturing challenges of CAR-MΦ, discussing autologous and allogeneic sources and the importance of stringent quality control. The potential synergies of integrating CAR-MΦ with existing cancer therapies like checkpoint inhibitors and conventional chemotherapeutics are examined to highlight possible enhanced treatment outcomes. Furthermore, regulatory pathways for CAR-MΦ therapies are scrutinized alongside established protocols for CAR-T cells, identifying unique considerations essential for clinical trials and market approval. Proposed safety monitoring frameworks aim to manage potential adverse events, such as cytokine release syndrome, crucial for patient safety. Consolidating current research and clinical insights, this review seeks to refine CAR-MΦ therapeutic applications, overcome barriers, and suggest future research directions to transition CAR-MΦ therapies from experimental platforms to standard cancer care options.

Background: Chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable success in hematologic malignancies but faces significant limitations in gastrointestinal tumors due to the immunosuppressive tumor microenvironment (TME). Indoleamine 2,3-dioxygenase 1 (IDO1), a key enzyme in the TME, suppresses T cell efficacy by catalyzing tryptophan degradation to kynurenine (Kyn), leading to T cell exhaustion and reduced cytotoxicity. This study investigates the role of IDO1 inhibition in overcoming metabolic suppression by kynurenine and enhancing Claudin18.2 (CLDN18.2) CAR-T cell therapy in gastric and pancreatic adenocarcinoma models. Methods: We evaluated the impact of genetic knockdown and pharmacological inhibition of IDO1 (using epacadostat) on CAR-T cell functionality, including cytokine production and exhaustion marker expression. The effects of fludarabine and cyclophosphamide preconditioning on IDO1 expression, CAR-T cell infiltration, and antitumor activity was also examined. In vivo tumor models of gastric and pancreatic adenocarcinomas were used to assess the efficacy of combining IDO1 inhibition with CLDN18.2-CAR-T therapy. Results: IDO1 inhibition significantly enhanced CAR-T cell function by increasing cytokine production, reducing exhaustion markers by decreasing TOX expression and improving tumor cell lysis. Preconditioning with fludarabine and cyclophosphamide further suppressed IDO1 expression in the TME, facilitating enhanced CAR-T cell infiltration. In vivo studies demonstrated that combining IDO1 inhibition with CAR-T therapy led to robust tumor growth suppression and prolonged survival in gastric and pancreatic tumor models. Conclusions: Targeting IDO1 represents a promising strategy to overcome immunosuppressive barriers in gastrointestinal cancers, improving the efficacy of CLDN18.2-CAR-T therapy. These findings highlight the potential for integrating IDO1 inhibition into CAR-T treatment regimens to address resistance in treatment-refractory cancers. [ABSTRACT FROM AUTHOR]

Introduction: Colorectal cancer (CRC), characterized by its complex genetic heterogeneity and varied responses to treatment, is a leading cause of cancer-related mortality worldwide. The role of N1-methyladenosine (m1A)-related genes in tumor biology remains underexplored. This study aimed to investigate the prognostic value of m1A-related genes in CRC, characterize their role in tumor molecular subtyping, and explore their influence on the tumor microenvironment (TME) and immune infiltration. Methods: To identify prognostic markers, univariate Cox analysis was performed using multiple datasets, including TCGA and GEO, identifying 43 m1A-related genes. Four distinct molecular subtypes of CRC were defined based on the expression of these genes using non-negative matrix factorization (NMF). Immune infiltration analysis was conducted, and the TIDE algorithm was used to predict response to immune checkpoint inhibitors (ICIs). Furthermore, a prognostic model based on m1A-related genes was constructed and validated across multiple datasets. Results: The results demonstrated that the four CRC molecular subtypes exhibited significant differences in survival outcomes and clinical characteristics. Stromal cells showed higher m1A scores, suggesting a regulatory role in the TME. There was a positive correlation between m1A-related gene expression and immune checkpoint genes. Moreover, the constructed prognostic model showed robust predictive performance and outperformed other recently published models. Discussion: The findings suggest that m1A-related genes are not only valuable biomarkers for CRC prognosis but also have significant implications for the immune landscape and could serve as potential targets for therapeutic intervention, particularly in the context of immunotherapy. For instance, SLC12A2 was found to enhance invasion, proliferation, and migration of colorectal cancer cells while inhibiting apoptosis. Further studies are needed to understand the functional roles of m1A modifications across different cell types within the TME. [ABSTRACT FROM AUTHOR]

Introduction: Tumor drug resistance, particularly immune-mediated resistance, poses a significant challenge in cancer therapy, especially in clear-cell renal cell carcinoma (ccRCC), the most common and aggressive subtype of renal cancer. Tumor-infiltrating immune cells (TIICs) within the tumor microenvironment (TME) play pivotal roles in tumor progression, immune evasion, and therapy resistance. This study explores the prognostic and therapeutic implications of TIICs in ccRCC, aiming to uncover molecular underpinnings and potential strategies to counter drug resistance. Methods: Integrative analyses of transcriptomic and single-cell RNA sequencing data from multiple cohorts were employed to characterize immune and metabolic landscapes in ccRCC. Machine learning algorithms were utilized to identify key TIIC-related RNAs (TIIC-RNAs) associated with prognosis and therapeutic response. The constructed prognostic model was validated across independent datasets. Additionally, the correlation between TIIC score and immune checkpoint expression, metabolic alterations, and genomic mutations was investigated. Results: The TIIC-based model demonstrated superior predictive performance for patient outcomes compared to 53 published models. High TIIC feature score correlated with increased immune infiltration, inflammatory responses, and poor survival. In contrast, low score was associated with enhanced responses to immune checkpoint inhibitors. Significant metabolic reprogramming, including lipid and sulfur metabolism, and distinct genomic alterations, such as BAP1 mutations, were linked to TIIC score. Conclusion: Our findings underscore the pivotal role of TIIC-RNAs in mediating drug resistance in ccRCC. The prognostic model provides valuable insights into immune and metabolic mechanisms underlying therapy resistance, offering a foundation for developing precision therapeutics targeting the TME. [ABSTRACT FROM AUTHOR]

Lung squamous carcinoma (LUSC) is a highly heterogeneous disease. However, the tumor microenvironment (TME) landscape and clinical characteristics for LUSC have not yet been elucidated. To map the TME and clinical characteristics of LUSC, we performed single-cell RNA sequencing for 504 LUSC samples on basis of TCGA and Gene Expression Omnibus. We introduced the computational algorithms "ESTIMATE" and "CIBERSORT" to analyze immune cell infiltration and immune-checkpoint-related gene signatures in various LUSC clusters. Weighted gene co-expression network analysis was used to explore the connections between molecular characteristics and clinical traits in LUSC. A prognostic model was constructed by performing multivariate COX. Two gene clusters exhibiting disparate immune and clinical characteristics were identified. Our findings indicate that patients in cluster 2, who have a more favorable prognosis, exhibit immune characteristics such as elevated levels of immunosuppression-associated M2 macrophages, resting memory CD4 T cells, resting dendritic cells (DC), and TNFRSF4, alongside reduced infiltration of activated DC and lower expression of TNFRSF18.Whereafter, the Risk Score model was built on basis of 3-DEGs signature consisted of cystatin C (CST3), transglutaminase type 2 (TGM2), JUN, which were proved by q-PCR and immunofluorescence. Besides, high-Risk Score may be responsible for poor prognosis in LUSC patients. Our study identified that tumor-infiltrating immune cell subtypes and the Risk Score model might shed light on the heterogeneity in LUSC patients. The TME, three DEGs and Risk Score can effectively serve as biomarkers to elucidate the immune landscape and predict prognosis in LUSC patients. They may provide insights to the investigations on therapeutic strategies for LUSC. [ABSTRACT FROM AUTHOR]

Advanced ovarian cancer (AOC) is prone to recurrence, which can be attributed to drug resistance. Drug resistance may be related to the tumor microenvironment (TME), including the immune and non-immune TME. In the immune TME, the immune effector cells such as dendritic cells (DCs), M1-like tumor-associated macrophages (M1-TAMs), and T cells are inhibited. In contrast, immunosuppressive cells such as M2-like tumor-associated macrophages (M2-TAMs), myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs) are activated. These changes make it difficult to produce immune effects and affect the efficacy of chemo-immunotherapy. In the non-immune TME, mechanisms such as apoptosis inhibition, DNA damage response (DDR), and epithelial-mesenchymal transition (EMT) can promote tumor growth, metastasis, and drug resistance. Despite the challenges posed by the TME in the treatment of AOC, the unique biological advantages of nanoparticles (NPs) make it possible to regulate the TME. NPs can stimulate the immune responses of M1-TAMs, DCs, and T cells while reducing the infiltration of immune suppressive cells such as M2-TAMs and Tregs, thereby regulating the AOC immune TME. In addition, NPs can regulate the non-immune TME by reducing apoptosis in AOC cells, inhibiting homologous recombination (HR) repair, reversing EMT, and achieving the effect of reversing drug resistance. In summary, the application of NPs provides some new venues for clinical treatment in AOC. [ABSTRACT FROM AUTHOR]

Over the past decades, significant progress has been made in the understanding of non-small cell lung cancer (NSCLC) biology and tumor progression mechanisms, resulting in the development of novel strategies for early detection and wide-ranging care approaches. Since their introduction, over 20 years ago, targeted therapies with tyrosine kinase inhibitors (TKIs) have revolutionized the treatment landscape for NSCLC. Nowadays, targeted therapies remain the gold standard for many patients, but still they suffer from many adverse effects, including unexpected toxicity and intrinsic acquired resistance mutations, which lead to relapse. The adoption of immune checkpoint inhibitors (ICIs) in 2015, has offered exceptional survival benefits for patients without targetable alterations. Despite this notable progress, challenges remain, as not all patients respond favorably to ICIs, and resistance to therapy can develop over time. A crucial factor influencing clinical response to immunotherapy is the tumor microenvironment (TME). The TME is pivotal in orchestrating the interactions between neoplastic cells and the immune system, influencing tumor growth and treatment outcomes. In this review, we discuss how the understanding of this intricate relationship is crucial for the success of immunotherapy and survey the current state of immunotherapy intervention, with a focus on forthcoming and promising chimeric antigen receptor (CAR) T cell therapies in NSCLC. The TME sets major obstacles for CAR-T therapies, creating conditions that suppress the immune response, inducing T cell exhaustion. To enhance treatment efficacy, specific efforts associated with CAR-T cell therapy in NSCLC, should definitely focus TME-related immunosuppression and antigen escape mechanisms, by combining CAR-T cells with immune checkpoint blockades. [ABSTRACT FROM AUTHOR]

Krüppel-like factors (KLFs) regulate various biological processes such as cell proliferation, migration, invasion, and differentiation as gene transcription factors. Signaling pathways which mediated by KLF4 and KLF4 have a sophisticated role in tumors due to multiple factors, including the types or stage of tumors. KLF4 plays a promoter role in tumorigenesis and development, or tumor suppressor as a context-dependent anti- and pro-inflammatory factor. KLF4 over-expression increases CD8+T cell differentiation and enhances the antitumor immunity. This review aims to provide information about the relationship of KLF4 in immunity with tumors and to guide the future study. [ABSTRACT FROM AUTHOR]

Background: Transforming growth factor (TGF)-ß1 is a pleiotropic cytokine that can promote tumor growth and suppress antitumor immune responses. Latent TGF-ß1 associates with glycoprotein-A repetition predominant (GARP) on the surface of regulatory T cells prior to its activation and release. Livmoniplimab is a monoclonal antibody (mAb) that binds the GARP:TGF-ß1 complex to inhibit activation and release of TGF-ß1. It is in clinical development in combination with budigalimab, an anti-programmed cell death protein 1 Fc-modified mAb. The first-in-human, phase 1, dose-escalation results are presented herein (ClinicalTrials.gov : NCT03821935). Methods: The dose-escalation phase enrolled adult patients with advanced solid tumors. Patients received escalating doses of livmoniplimab ranging from 3mg to 1500mg, once every 2 weeks (Q2W), as monotherapy or in combination with a 500mg fixed dose of budigalimab Q4W. The primary objective of the dose escalation was to determine the recommended phase 2 dose. Secondary objectives were to assess safety and pharmacokinetics (PK), and exploratory objectives included evaluating preliminary efficacy. Results: Fifty-seven patients enrolled in the dose escalation: 23 in monotherapy cohorts and 34 in combination therapy cohorts. Dose-limiting toxicities were limited, no maximum tolerated dose was reached, and the maximum administered dose of 1500mg was selected for dose expansion. The most common adverse events reported in monotherapy-treated patients were fatigue, anemia, and nausea, and those in combination therapy-treated patients were pruritus, fatigue, nausea, and anemia. Livmoniplimab exhibited dose-proportional PK, and peripheral blood biomarker data demonstrated saturation of the GARP:TGF-ß1 complex on platelets at livmoniplimab doses within the linear PK range. No objective tumor responses were observed in the monotherapy dose escalation. However, the objective response rate was 15% in the combination dose escalation, with a median response duration of 8.4 months. Conclusion: Livmoniplimab was well-tolerated as monotherapy and in combination with budigalimab in the dose-escalation phase. Encouraging preliminary efficacy was demonstrated in the combination dose escalation in heavily pretreated patients, supporting further development of this novel drug combination in patients with advanced solid tumors. [ABSTRACT FROM AUTHOR]

Dietary behaviors significantly influence tumor progression, with increasing focus on high-salt diets (HSD) in recent years. Traditionally, HSD has been regarded as a major risk factor for multiple health issues, including hypertension, cardiovascular disease, kidney disease, cancer, and osteoporosis. However, recent studies have uncovered a novel aspect of HSD, suggesting that HSD may inhibit tumor growth in specific pathological conditions by modulating the activity of immune cells that infiltrate tumors and enhancing the effectiveness of PD-1 immunotherapy. This review focused on the duel molecular mechanisms of HSD in cancer development, which are based on the tumor microenvironment, the gut microbiota, and the involvement of sodium transporter channels. The objective of this review is to explore whether HSD could be a potential future oncological therapeutic strategy under specific situation. [ABSTRACT FROM AUTHOR]

The editorial discusses tertiary lymphoid structures (TLS) in the tumor immune microenvironment, highlighting their role in recruiting and activating immune cells within solid tumors. TLS are recognized as significant sources of tumor-infiltrating lymphocytes (TILs) and are associated with improved patient prognosis. The research explores TLS in various solid tumors, emphasizing their predictive value for immunotherapy response, the importance of assessing TLS maturity and density, and the link between immune checkpoint pathways and TLS formation. Further studies are needed to validate these findings and enhance understanding of TLS in cancer immunotherapy. [Extracted from the article]

Glioblastoma's (GB) complex tumor microenvironment (TME) promotes its progression and resistance to therapy. A critical component of TME is the extracellular matrix (ECM), which plays a pivotal role in promoting the tumor's invasive behavior and aggressiveness. Nanotechnology holds significant promise for GB treatment, with the potential to address challenges posed by both the blood-brain barrier and the GB ECM. By enabling targeted delivery of therapeutic and diagnostic agents, nanotechnology offers the prospect of improving treatment efficacy and diagnostic accuracy at the tumor site. This review provides a comprehensive exploration of GB, including its epidemiology, classification, and current treatment strategies, alongside the intricacies of its TME. It highlights nanotechnology-based strategies, focusing on nanoparticle formulations such as liposomes, polymeric nanoparticles, and gold nanoparticles, which have shown promise in GB therapy. Furthermore, it explores how different emerging nanotechnology strategies modulate the ECM to overcome the challenges posed by its high density, which restricts drug distribution within GB tumors. By emphasizing the intersection of nanotechnology and GB ECM, this review underscores an innovative approach to advancing GB treatment. It addresses the limitations of current therapies, identifies new research avenues, and emphasizes the potential of nanotechnology to improve patient outcomes. [ABSTRACT FROM AUTHOR]

In light of the emerging breakthroughs in cancer biology, drug discovery, and personalized medicine, Tumor-on-Chip (ToC) platforms have become pivotal tools in current biomedical research. This study introduced a novel rapid prototyping approach for the fabrication of a ToC device using laser-patterned poly(methyl methacrylate) (PMMA) layers integrated with a polylactic acid (PLA) electrospun scaffold, enabling dynamic drug delivery and the assessment of therapeutic efficacy in cancer cells. Traditional drug screening methods, such as conventional cell cultures, mimic certain aspects of cancer progression but fail to capture critical features of the tumor microenvironment (TME). While animal models offer a closer approximation of tumor complexity, they are limited in their ability to predict human drug responses. Here, we evaluated the ability of our ToC device to recapitulate the interactions between cancer and TME cells and its efficacy in evaluating the drug response of breast cancer cells. The functional design of the proposed ToC system offered substantial potential for a wide range of applications in cancer research, significantly accelerating the preclinical assessment of new therapeutic agents. [ABSTRACT FROM AUTHOR]

Simple Summary: Patient-derived organoids (PDOs) have revolutionized cancer research by offering three-dimensional models that retain the genetic and architectural features of primary tumors. The integration of invariant Natural Killer T (iNKT) cells into PDO platforms presents an innovative approach for studying immune–tumor dynamics and advancing cancer immunotherapy. iNKT cells, known for their ability to modulate immune responses and target tumors, face challenges in suppressive tumor microenvironments (TMEs), which limit their therapeutic potential. PDOs provide a physiologically relevant platform to explore strategies to counteract TME-induced immunosuppression, such as modulating tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), or tumor metabolism. Additionally, PDOs enable the testing of combination therapies, including iNKT cell-based treatments and immune checkpoint inhibitors, to amplify anti-tumor efficacy. While the integration of iNKT cells with PDOs remains underexplored, ongoing advancements in multi-omics, imaging, and automation technologies promise to enhance this approach, paving the way for personalized cancer treatments. Invariant Natural Killer T (iNKT) cells are a unique subset of T cells that bridge innate and adaptive immunity, displaying potent anti-tumor properties through cytokine secretion, direct cytotoxicity, and recruitment of immune effector cells such as CD8+ T cells and NK cells. Despite their therapeutic potential, the immunosuppressive tumor microenvironment (TME), characterized by regulatory T cells, myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs), limits iNKT cell efficacy. Patient-derived organoid (PDO) platforms provide an innovative model for dissecting these complex interactions and evaluating strategies to reinvigorate iNKT cell functionality within the TME. PDOs closely mimic the genetic, phenotypic, and structural characteristics of primary tumors, enabling the study of tumor–immune dynamics. Integrating iNKT cells into PDOs offers a robust platform for investigating CD1d-mediated interactions, Th1-biased immune responses driven by glycolipid analogs like α-GalCer, and combination therapies such as immune checkpoint inhibitors. Additionally, PDO systems can assess the effects of metabolic modulation, including reducing lactic acid accumulation or targeting glutamine pathways, on enhancing iNKT cell activity. Emerging innovations, such as organoid-on-a-chip systems, CRISPR-Cas9 gene editing, and multi-omics approaches, further expand the potential of PDO–iNKT platforms for personalized immunotherapy research. Although the application of iNKT cells in PDOs is still undeveloped, these systems hold immense promise for bridging preclinical studies and clinical translation. By addressing the challenges of the TME and optimizing therapeutic strategies, PDO–iNKT platforms offer a transformative avenue for advancing cancer immunotherapy and personalized medicine. [ABSTRACT FROM AUTHOR]

Nanozymes can improve reactive oxygen species (ROS)-based cancer therapies by targeting cancer cells' antioxidant defense mechanisms, particularly glutathione (GSH) depletion, to overcome ROS-resistant cancer cells. Nanozymes, innovative enzyme-mimetic nanomaterials, can generate ROS, alter the tumor microenvironment (TME), and synergize with photodynamic therapy (PDT), chemodynamic therapy (CDT), radiotherapy, and immunotherapy. This review shows how nanozymes catalyze ROS generation, selectively deplete GSH, and target cancer elimination, offering clear advantages over standard therapies. Nanozymes selectively target cancer cells' antioxidant defenses to improve PDT, CDT, and radiation therapies. To maximize nanozyme-based cancer treatment efficacy, biodistribution, biocompatibility, and tumor heterogeneity must be assessed. To improve cancer treatment, multifunctional, stimuli-responsive nanozymes and synergistic combination drugs should be developed. [ABSTRACT FROM AUTHOR]

The tumor microenvironment (TME) is integral to cancer progression, impacting metastasis and treatment response. It consists of diverse cell types, extracellular matrix components, and signaling molecules that interact to promote tumor growth and therapeutic resistance. Elucidating the intricate interactions between cancer cells and the TME is crucial in understanding cancer progression and therapeutic challenges. A critical process induced by TME signaling is the epithelial-mesenchymal transition (EMT), wherein epithelial cells acquire mesenchymal traits, which enhance their motility and invasiveness and promote metastasis and cancer progression. By targeting various components of the TME, novel investigational strategies aim to disrupt the TME's contribution to the EMT, thereby improving treatment efficacy, addressing therapeutic resistance, and offering a nuanced approach to cancer therapy. This review scrutinizes the key players in the TME and the TME's contribution to the EMT, emphasizing avenues to therapeutically disrupt the interactions between the various TME components. Moreover, the article discusses the TME's implications for resistance mechanisms and highlights the current therapeutic strategies toward TME modulation along with potential caveats. [ABSTRACT FROM AUTHOR]

Background: The metabolism of stearoyl-GPE plays a key role in the liver metastasis of gastric cancer. This investigation delves into the mechanisms underlying the intricate tumor microenvironment (TME) heterogeneity triggered by stearoyl metabolism in gastric cancer with liver metastasis (LMGC), offering novel perspectives for LMGC. Objective: Utilizing Mendelian randomization, we determined that stearoyl metabolism significantly contributes to the progression of gastric cancer (GC). Following this, bulk transcriptome analyses and single-cell multiomics techniques to investigate the roles of stearoyl-GPE metabolism-related genes, particularly NCOA4, in regulating LMGC TME. Results: Our analysis highlights the crucial role of stearoyl metabolism in modulating the complex microenvironment of LMGC, particularly impacting monocyte cells. Through single-cell sequencing and spatial transcriptomics, we have identified key metabolic genes specific to stearoyl metabolism within the monocyte cell population, including NCOA4. Regarding the relationship between ferroptosis, stearoyl metabolism, and LMGC findings, it is plausible that stearoyl metabolism and LMGC pathways intersect with mechanisms involved in ferroptosis. Ferroptosis, characterized by iron-dependent lipid peroxidation, represents a regulated form of cell death. The activity of Stearoyl-CoA desaturase (SCD), a critical enzyme in stearoyl metabolism, has been associated with the modulation of lipid composition and susceptibility to ferroptosis. Furthermore, the LMGC is integral to cellular processes related to oxidative stress and lipid metabolism, both of which are significant factors in the context of ferroptosis. Conclusion: This study enhances the understanding of the relationship between stearoyl metabolism and ferroptosis in promoting liver metastasis of gastric cancer and its role in the regulation of tumor heterogeneity. In addition, this study contributes to a deeper understanding of the dynamics of gastric cancer tumor microenvironment (TME) and provides a basis for the development of better interventions to combat cancer metastasis. [ABSTRACT FROM AUTHOR]

Background: Patient-derived lung cancer organoids (PD-LCOs) demonstrate exceptional potential in preclinical testing and serve as a promising model for the multimodal management of lung cancer. However, certain lung cancer cells derived from patients exhibit limited capacity to generate organoids due to inter-tumor or intra-tumor variability. To overcome this limitation, we have created an in vitro system that employs mesenchymal stromal cells (MSCs) or fibroblasts to serve as a supportive scaffold for lung cancer cells that do not form organoids. Methods: We successfully established an MSCs/fibroblast co-culture system to form LCOs. We analyzed the morphological and histological similarities between LCOs co-cultured with fibroblast and primary lung cancer lesions through HE and IF staining. We evaluated whether LCOs co-cultured with fibroblast retained the original genetic mutations of their source tumors based on WES. RNA sequencing was used to analyze the differences in gene expression profiles between LCOs co-cultured with fibroblast and paracancerous organoids (POs). Importantly, we have successfully validated the impact of Kindlin-2 on the regulation of MSCs in organoid formation through lentiviral vector-mediated interference or overexpression of kindlin-2. Results: Our findings demonstrate that the addition of MSCs/fibroblasts to three tumor samples, initially incapable of forming organoids by traditional methods, successfully facilitated the cultivation of tumor organoids. Importantly, these organoids co-cultured with fibroblast faithfully recapitulate the tissue morphology of original lung tumors and replicate the genetic profile observed in the parental tumors even after prolonged in vitro culture. Moreover, drug responses exhibited by these organoids co-cultured with MSCs/fibroblasts are consistent with those observed in the original tumors. Mechanistically, we have also identified kindlin-2 as a crucial regulator linking extracellular matrix (ECM) and mitochondria that influence MSC/fibroblast-mediated support for tumor organoid formation. Conclusion: The results obtained from our research enhance the understanding of the mechanisms implicated in the formation of tumor organoids and aid in creating stronger patient-specific tumor organoid models. This advancement supports the refinement of personalized drug response assessments for use in clinical settings. [ABSTRACT FROM AUTHOR]

Cervical cancer (CESC) presents significant clinical challenges due to its complex tumor microenvironment (TME) and varied treatment responses. This study identified undifferentiated M0 macrophages as high-risk immune cells critically involved in CESC progression. Co-culture experiments further demonstrated that M0 macrophages significantly promoted HeLa cell proliferation, migration, and invasion, underscoring their pivotal role in modulating tumor cell behavior within the TME. A nine-gene prognostic model constructed from immune gene signatures highlighted CXCL8 as a key regulator of M0 macrophage behavior. Functional experiments demonstrated that CXCL8 knockdown in M0 macrophages inhibited their proliferation, shifted polarization toward an M1-dominant phenotype, and reduced tumor-promoting M2 polarization. Co-culture experiments with CXCL8-deficient M0 macrophages further revealed a suppression of HeLa cell proliferation, migration, and invasion. These findings position M0 macrophages as central regulators within the TME and suggest that targeting pathways like CXCL8 could provide novel therapeutic strategies for improving outcomes in CESC patients. [ABSTRACT FROM AUTHOR]

Recent developments in single-cell multi-omics technologies have provided the ability to identify diverse cell types and decipher key components of the tumor microenvironment (TME), leading to important advancements toward a much deeper understanding of how tumor microenvironment heterogeneity contributes to cancer progression and therapeutic resistance. These technologies are able to integrate data from molecular genomic, transcriptomic, proteomics, and metabolomics studies of cells at a single-cell resolution scale that give rise to the full cellular and molecular complexity in the TME. Understanding the complex and sometimes reciprocal relationships among cancer cells, CAFs, immune cells, and ECs has led to novel insights into their immense heterogeneity in functions, which can have important consequences on tumor behavior. In-depth studies have uncovered immune evasion mechanisms, including the exhaustion of T cells and metabolic reprogramming in response to hypoxia from cancer cells. Single-cell multi-omics also revealed resistance mechanisms, such as stromal cell-secreted factors and physical barriers in the extracellular matrix. Future studies examining specific metabolic pathways and targeting approaches to reduce the heterogeneity in the TME will likely lead to better outcomes with immunotherapies, drug delivery, etc., for cancer treatments. Future studies will incorporate multi-omics data, spatial relationships in tumor micro-environments, and their translation into personalized cancer therapies. This review emphasizes how single-cell multi-omics can provide insights into the cellular and molecular heterogeneity of the TME, revealing immune evasion mechanisms, metabolic reprogramming, and stromal cell influences. These insights aim to guide the development of personalized and targeted cancer therapies, highlighting the role of TME diversity in shaping tumor behavior and treatment outcomes. [ABSTRACT FROM AUTHOR]

Human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HPV-positive HNSCC) has distinct biological characteristics from HPV-negative HNSCC. Using an AI-based analytical platform on meta cohorts, we profiled expression patterns of viral transcripts and HPV viral genome integration, and classified the tumor microenvironment (TME). Unsupervised clustering analysis revealed five distinct and novel TME subtypes across patients (immune-enriched, highly immune and B-cell enriched, fibrotic, immune-desert, and immune-enriched luminal). These TME subtypes were highly correlated with patient prognosis. In order to understand specific factors associated with prognosis, we used the unsupervised clustering of an HPV-positive HNSCC cohort from The Cancer Genome Atlas (TCGA) (n = 53) based on HPV transcript expression, and identified four HPV-related subtypes (E2/E5, E6/E7, E1/E4 and L1/L2). Utilizing both viral transcript and TME subtypes, we found that the E2/E5 HPV subtype was associated with an immune-enriched TME and had a higher overall survival rate compared to other subtypes. The E2/E5 subtype was also enriched for samples without HPV-genome integration, suggesting that the episomal HPV status and E2/E5 expression pattern may be associated with an inflamed microenvironment and improved prognosis. In contrast, E6/E7 subtype samples were associated with the fibrotic and immune-desert TME subtypes, with lower values of T-cell and B-cell gene expression signatures and lower overall survival. Both E1/E4 and L1/L2 subtypes were associated with the immune-enriched luminal subtype. Our results suggest that HPV-transcript expression patterns may drive the modulation of the TME, and thereby impact prognosis. [ABSTRACT FROM AUTHOR]

Abstract Introduction Tumor drug resistance, particularly immune-mediated resistance, poses a significant challenge in cancer therapy, especially in clear-cell renal cell carcinoma (ccRCC), the most common and aggressive subtype of renal cancer. Tumor-infiltrating immune cells (TIICs) within the tumor microenvironment (TME) play pivotal roles in tumor progression, immune evasion, and therapy resistance. This study explores the prognostic and therapeutic implications of TIICs in ccRCC, aiming to uncover molecular underpinnings and potential strategies to counter drug resistance. Methods Integrative analyses of transcriptomic and single-cell RNA sequencing data from multiple cohorts were employed to characterize immune and metabolic landscapes in ccRCC. Machine learning algorithms were utilized to identify key TIIC-related RNAs (TIIC-RNAs) associated with prognosis and therapeutic response. The constructed prognostic model was validated across independent datasets. Additionally, the correlation between TIIC score and immune checkpoint expression, metabolic alterations, and genomic mutations was investigated. Results The TIIC-based model demonstrated superior predictive performance for patient outcomes compared to 53 published models. High TIIC feature score correlated with increased immune infiltration, inflammatory responses, and poor survival. In contrast, low score was associated with enhanced responses to immune checkpoint inhibitors. Significant metabolic reprogramming, including lipid and sulfur metabolism, and distinct genomic alterations, such as BAP1 mutations, were linked to TIIC score. Conclusion Our findings underscore the pivotal role of TIIC-RNAs in mediating drug resistance in ccRCC. The prognostic model provides valuable insights into immune and metabolic mechanisms underlying therapy resistance, offering a foundation for developing precision therapeutics targeting the TME.

Cell-based immunotherapies (CBIs), notably exemplified by chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapy, have emerged as groundbreaking approaches for cancer therapy. Nevertheless, akin to various other therapeutic modalities, tumor cells employ counterstrategies to manifest immune evasion, thereby circumventing the impact of CBIs. This phenomenon is facilitated by an intricately immunosuppression entrenched within the tumor microenvironment (TME). Principal mechanisms underpinning tumor immune evasion from CBIs encompass loss of antigens, downregulation of antigen presentation, activation of immune checkpoint pathways, initiation of anti-apoptotic cascades, and induction of immune dysfunction and exhaustion. In this review, we delve into the intrinsic mechanisms underlying the capacity of tumor cells to resist CBIs and proffer prospective stratagems to navigate around these challenges.

Abstract Chimeric antigen receptor T (CAR-T) cell therapy has shown remarkable success in hematologic malignancies but has encountered challenges in effectively treating solid tumors. One major obstacle is the presence of the immunosuppressive tumor microenvironment (TME), which is mainly built by myeloid-derived suppressor cells (MDSCs). Recent studies have shown that MDSCs have a detrimental effect on CAR-T cells due to their potent immunosuppressive capabilities. Targeting MDSCs has shown promising results to enhance CAR-T immunotherapy in preclinical solid tumor models. In this review, we first highlight that MDSCs increase tumor proliferation, transition, angiogenesis and encourage circulating tumor cells (CTCs) extravasation leading to tumor progression and metastasis. Moreover, we describe the main characteristics of the immunosuppressive activities of MDSCs on T cells in TME. Most importantly, we summarize targeting therapeutic strategies of MDSCs in CAR-T therapies against solid tumors. These strategies include (1) therapeutic targeting of MDSCs through small molecule inhibitors and large molecule antibodies; (2) CAR-T targeting cancer cell antigen combination with MDSC modulatory agents; (3) cytokine receptor antigen-targeted CAR-T indirectly or directly targeting MDSCs reshapes TME; (4) modified natural killer (NK) cells expressing activating receptor directly targeting MDSCs; and (5) CAR-T directly targeting MDSC selective antigens. In the near future, we are expected to witness the improvement of CAR-T cell therapies for solid tumors by targeting MDSCs in clinical practice.

Abstract MicroRNAs (miRNAs) emerge as critical regulators of CD8 + T cell function within the complex tumor microenvironment (TME). This review explores the multifaceted interplay between miRNAs and CD8 + T cells across various cancers. We discuss how specific miRNAs influence CD8 + T cell activation, recruitment, infiltration, and effector function. Dysregulation of these miRNAs can contribute to CD8 + T cell exhaustion and immune evasion, hindering anti-tumor immunity. Conversely, manipulating miRNA expression holds promise for enhancing CD8 + T cell activity and improving cancer immunotherapy outcomes. We delve into the role of miRNAs in CD8 + T-cell function across different cancer types, including gliomas, gastric and colon cancer, oral squamous cell carcinoma, thyroid carcinoma, lymphomas, melanoma, breast cancer, renal cell carcinoma, ovarian cancer, uterine corpus endometrial cancer, bladder cancer, acute myeloid leukemia, chronic myelogenous leukemia, and osteosarcoma. Additionally, we explore how extracellular vesicles and cytokines modulate CD8 + T-cell function through complex interactions with miRNAs. Finally, we discuss the potential impact of radiotherapy and specific drugs on miRNA expression and CD8 + T-cell activity within the TME. This review highlights the immense potential of targeting miRNAs to manipulate CD8 + T-cell activity for the development of novel and improved cancer immunotherapies. Graphical Abstract