Cancer-associated fibroblasts (CAFs), as the "architect" of the immune microenvironment in lung cancer, play a multidimensional role in tumor progression and immune regulation. In this review, we summarize the heterogeneity of the origin and the molecular phenotype of CAFs in lung cancer, and explore the complex interactions between CAFs and multiple components of the tumor microenvironment, including the regulatory relationships with innate immune cells (e.g., tumor-associated macrophages, tumor-associated neutrophils), adaptive immune cells (e.g., T cells), and extracellular matrix (ECM). CAFs significantly influence tumor progression and immunomodulation through the secretion of cytokines, remodeling of the ECM, and the regulation of immune cell function significantly affects the immune escape and treatment resistance of tumors. In addition, this review also deeply explored the synergistic regulatory relationship between CAF and radiotherapy, revealing the key role of CAF in radiotherapy-induced remodeling of the immune microenvironment, which provides a new perspective for optimizing the comprehensive treatment strategy of lung cancer. By comprehensively analyzing the multidimensional roles of CAF and its interaction with radiotherapy, this review aims to provide a theoretical basis for the precise regulation of the immune microenvironment and clinical treatment of lung cancer.

The interaction between stromal cells and the tumor immune microenvironment (TIME) is acknowledged as a critical driver in the progression of prostate cancer (PCa). Monoamine oxidase A (MAOA), a mitochondrial enzyme that catalyzes the degradation of monoamine neurotransmitters and dietary amines, has been linked to the promotion of prostate tumorigenesis, particularly when upregulated in stromal cells. However, the detailed mechanisms of MAOA's interaction with TIME have not been fully elucidated.

We reanalyzed a single-cell sequencing dataset to evaluate the role of MAOA in the stroma, verify the impact of stromal MAOA alterations on CD8+ T cell responses by co-culturing stromal cells and immune cells in vitro. Furthermore, C57BL/6J mouse subcutaneous transplant tumor models and dual humanized mouse models were established to investigate the function of MAOA in vivo and the potential of its inhibitors for immunotherapy.

Our study demonstrates that inhibiting MAOA in stromal cells facilitates the conversion of myofibroblastic cancer-associated fibroblasts (myCAFs), thereby improving the immunosuppressive environment of PCa. The strategic combination of MAOA inhibition with immune checkpoint inhibitors elicits a synergistic antitumor effect. Specifically, MAOA inhibition in stromal cells leads to increased production of WNT5A, which subsequently activates the cytotoxic capacity of CD8+ T cells through the Ca2+-NFATC1 signaling pathway.

Our findings highlight the critical role of MAOA in modulating cancer-associated fibroblasts within the PCa immune microenvironment, presenting a novel therapeutic strategy to augment the efficacy of immunotherapy for PCa.

Tumor-nerve interactions play a critical role in tumor progression, metastasis, and treatment resistance, redefining our understanding of the tumor microenvironment. This review provides a comprehensive analysis of how the peripheral and central nervous systems contribute to cancer biology, focusing on mechanisms of neural invasion, immune evasion, and tumor adaptation. It has highlighted the emerging potential of repurposing nervous system-targeted drugs originally developed for neurodegenerative and autoimmune diseases as innovative cancer therapies. The review also addresses key challenges, including the limitations of current experimental models and the complexity of translating preclinical findings to clinical applications. By bridging the gap between neuroscience and oncology, this interdisciplinary study aims to discover novel therapeutic strategies to improve outcomes for cancer patients.

Breast cancer remains a significant global health challenge, with diverse subtypes and complex molecular mechanisms underlying its development and progression. This review comprehensively examines recent advances in breast cancer research, with a focus on classification, molecular pathways, and the role of heme oxygenases (HO), heme metabolism implications, and therapeutic innovations. The classification of breast cancer subtypes based on molecular profiling has significantly improved diagnosis and treatment strategies, allowing for tailored approaches to patient care. Molecular studies have elucidated key signaling pathways and biomarkers implicated in breast cancer pathogenesis, shedding light on potential targets for therapeutic intervention. Notably, emerging evidence suggests a critical role for heme oxygenases, particularly HO-1, in breast cancer progression and therapeutic resistance, highlighting the importance of understanding heme metabolism in cancer biology. Furthermore, this review highlights recent advances in breast cancer therapy, including targeted therapies, immunotherapy, and novel drug delivery systems. Understanding the complex interplay between breast cancer subtypes, molecular pathways, and innovative therapeutic approaches is essential for improving patient outcomes and developing more effective treatment strategies in the fight against breast cancer.

Brain metastases (BMs) are the most common intracranial tumors in adults and the major cause of cancer-related morbidity and mortality. The occurrence of BMs varies according to the type of primary tumors with most frequence in lung cancer, melanoma and breast cancer. Among of them, lung cancer has been reported to have a higher risk of BMs than other types of cancers with 40 ~ 50% of such patients will develop BMs during the course of disease. BMs lead to many neurological complications and result in a poor quality of life and short life span. Although the treatment strategies were improved for brain tumors in the past decades, the prognosis of BMs patients is grim. Poorly understanding of the molecular and cellular characteristics of BMs and the complicated interaction with brain microenvironment are the major reasons for the dismal prognosis of BM patients. Recent studies have enhanced understanding of the mechanisms of BMs. The newly identified potential therapeutic targets and the advanced therapeutic strategies have brought light for a better cure of BMs. In this review, we summarized the mechanisms of BMs during the metastatic course, the molecular and cellular landscapes of BMs, and the advances of novel drug delivery systems for overcoming the obstruction of blood-brain barrier (BBB). We further discussed the challenges of the emerging therapeutic strategies, such as synergistic approach of combining targeted therapy with immunotherapy, which will provide vital clues for realizing the precise and personalized medicine for BM patients in the future.

Esophageal squamous cell carcinoma (ESCC) is a common and aggressive subtype of esophageal cancer. This research investigates the functions of cancer-associated fibroblasts (CAFs) in the malignant phenotype of ESCC and probes the underpinning mechanism. Key CAF-associated proteins in ESCC were identified using bioinformatics analyses. ESCC cell lines were co-cultured with CAFs, followed by the addition of neutralizing antibodies against WNT family member 5A (WNT5A) (Anti-WNT5A; AW) and frizzled class receptor 5 (FZD5) (Anti-FZD5; AF), or a human recombinant protein of WNT5A (rWNT5A; rW). The effects of CAF stimulation and the neutralizing or recombinant proteins on the growth and dissemination of ESCC cells were investigated. In addition, ESCC cells were transplanted into nude mice for in vivo assessment of tumor growth and metastasis. WNT5A was identified as a CAF-associated protein linked to poor prognosis in ESCC. Co-culturing with CAFs augmented proliferation, mobility, and apoptosis resistance of ESCC cells. These effects were negated by the AW or AF but restored by rW. WNT5A interacted with FZD5 to activate the WNT signaling in ESCC cells. The rW treatment also enhanced tumorigenesis and metastasis of xenograft tumors in nude mice, with these effects diminished by AW or AF treatment. This study suggests that CAFs promote growth and dissemination of ESCC cell primarily through the secretion of WNT5A.

Background/Objectives: Cancer-associated fibroblasts (CAFs) in the tumor microenvironment have been reported to be closely associated with tumor progression in various types of cancer, including colorectal cancer (CRC). Periostin, a matricellular protein, was reported to be expressed on both cancer cells and surrounding tumor stromal cells, such as CAFs, and is regulated by Smad2/3 signaling. In this study, we aimed to clarify the clinicopathologic significance of periostin and Smad2/3 expression in CRC, with a particular focus on the tumor microenvironment. Methods: A total of 351 CRC patients were enrolled according to the inclusion and exclusion criteria. The expressions of periostin and Smad2/3 in the tumor specimens were examined by immunohistochemistry. Results: Periostin expression of CAFs and cancer cells in the 351 CRC cases was observed at 36.8% and 0.6%, respectively. Smad2/3 expression of CAFs and cancer cells was observed in 41.0% and 90.0%, respectively. In CAFs, high periostin expression was significantly correlated with high Smad2/3 expression, increased invasion depth, lymph node metastasis, venous invasion, advanced disease stage, and a higher rate of relapse. The prognoses of patients with periostin-positive CAFs were significantly poorer than those with periostin-negative CAFs (p < 0.001). The survival outcomes of stage 3 CRC patients with co-expression of periostin and Smad2/3 were significantly worse compared to those with stage 2 CRC. In the stage 3 group, multivariate analysis revealed that periostin was an independent prognostic factor, while univariate analysis showed that both periostin and Smad2/3 were significantly correlated with poor survival. Conclusions: These findings suggest that periostin is expressed mainly in CAFs in CRC and is correlated with Smad2/3 expression in CAFs. Periostin from CAFs might be associated with the malignant progression of CRC via Smad2/3 signaling.

Cholangiocarcinoma (CCA) remains a devastating malignancy and a significant challenge to treat. The majority of CCA patients are diagnosed at an advanced stage, making the disease incurable in most cases. The advent of high-throughput genetic sequencing has significantly improved our understanding of the molecular biology underpinning cancer. The identification of 'druggable' genetic aberrations and the development of novel targeted therapies against them is opening up new treatment strategies. Currently, 3 targeted therapies are approved for use in CCA; Ivosidenib in patients with IDH1 mutations and Infigratinib/Pemigatinib in those with FGFR2 fusions. As our understanding of the biology underpinning CCA continues to improve it is highly likely that additional targeted therapies will become available in the near future. This is important, as it is thought up to 40 % of CCA patients harbour a potentially actionable mutation. In this review we provide an overview of the molecular pathogenesis of CCA and highlight currently available and potential future targeted treatments.

The hepatocyte growth factor (HGF) along with its receptor (c-MET) are crucial in preserving standard cellular physiological activities, and imbalances in the c-MET signaling pathway can lead to the development and advancement of tumors. It has been extensively demonstrated that immune checkpoint inhibitors (ICIs) can result in prolonged remission in certain patients. Nevertheless, numerous preclinical studies have shown that MET imbalance hinders the effectiveness of anti-PD-1/PD-L1 treatments through various mechanisms. Consequently, clarifying the link between the c-MET signaling pathway and the tumor microenvironment (TME), as well as uncovering the effects of anti-MET treatment on ICI therapy, is crucial for enhancing the outlook for tumor patients. In this review, we examine the impact of abnormal activation of the HGF/c-MET signaling pathway on the control of the TME and the processes governing PD-L1 expression in cancer cells. The review thoroughly examines both clinical and practical evidence regarding the use of c-MET inhibitors alongside PD-1/PD-L1 inhibitors, emphasizing that focusing on c-MET with immunotherapy enhances the effectiveness of treating MET tumors exhibiting elevated PD-L1 expression.

Research into cancer treatment has been mainly focused on developing therapies to directly target cancer cells. Over the past decade, extensive studies have revealed critical roles of the tumour microenvironment (TME) in cancer initiation, progression, and drug resistance. Notably, cancer-associated fibroblasts (CAFs) have emerged as one of the primary contributors in shaping TME, creating a favourable environment for cancer development. Many preclinical studies have identified promising targets on CAFs, demonstrating remarkable efficacy of some CAF-targeted treatments in preclinical models. Encouraged by these compelling findings, therapeutic strategies have now advanced into clinical evaluation. We aim to provide a comprehensive review of relevant subjects on CAFs, including CAF-related markers and targets, their multifaceted roles, and current landscape of ongoing clinical trials. This knowledge can guide future research on CAFs and advocate for clinical investigations targeting CAFs.

In recent years, nano-drug delivery systems (Nano-DDS) that target the tumor microenvironment (TME) to overcome multidrug resistance (MDR) have become a research hotspot in the field of cancer therapy. By precisely targeting the TME and regulating its unique pathological features, such as hypoxia, weakly acidic pH, and abnormally expressed proteins, etc., these Nano-DDS enable effective delivery of therapeutic agents and reversal of MDR. This scientific research community is increasing its investment in the development of diversified systems and exploring their anti-drug resistance potential. Therefore, it is particularly important to conduct a comprehensive review of the research progress of TME-targeted Nano-DDS in recent years. After a brief introduction of TME and tumor MDR, the design principle and structure of liposomes, polymer micelles and inorganic nanocarriers are focused on, and their characteristics as TME-targeted nanocarriers are described. It also demonstrates how these systems break through the cancer MDR treatment through various targeting mechanisms, discusses their synthetic innovation, research results and resistance overcoming mechanisms. The review was concluded with deliberations on the key challenges and future outlooks of targeting TME Nano-DDS in cancer therapy.

Tumor vaccines, as an immunotherapeutic approach, harness the body's immune cells to provoke antitumor responses, which have shown promising efficacy in clinical settings. However, the immunosuppressive tumor microenvironment (TME) and the ineffective vaccine delivery systems hinder the progression of many vaccines beyond phase II trials. This article begins with a comprehensive review of the complex interactions between tumor vaccines and TME, summarizing the current state of vaccine clinical research. Subsequently, we review recent advancements in targeted vaccine delivery systems and explore biomaterial-based tumor vaccines as a strategy to improve the efficacy of both delivery systems and treatment. Finally, we have presented our perspectives on tumor vaccine development, aiming to advance the field towards the creation of more effective tumor vaccines.

Natural killer (NK) cells and dendritic cells (DCs) are critical mediators of anti-cancer immune responses. In addition to their individual roles, NK cells and DCs are involved in intercellular crosstalk which is essential for the initiation and coordination of adaptive immunity against cancer. However, NK cell and DC activity is often compromised in the tumor microenvironment (TME). Recently, much attention has been paid to one of the major components of the TME, the cancer-associated fibroblasts (CAFs), which not only contribute to extracellular matrix (ECM) deposition and tumor progression but also suppress immune cell functions. It is now well established that CAFs support T cell exclusion from tumor nests and regulate their cytotoxic activity. In contrast, little is currently known about their interaction with NK cells, and DCs. In this review, we describe the interaction of CAFs with NK cells and DCs, by secreting and expressing various mediators in the TME of adult solid tumors. We also provide a detailed overview of ongoing clinical studies evaluating the targeting of stromal factors alone or in combination with immunotherapy based on immune checkpoint inhibitors. Finally, we discuss currently available strategies for the selective depletion of detrimental CAFs and for a better understanding of their interaction with NK cells and DCs.

Peritumoral fibrosis is known to promote cancer progression and confer treatment resistance in various solid tumors. Consequently, developing accurate cancer research and drug screening models that replicate the structure and function of a fibrosis-surrounded tumor mass is imperative. Previous studies have shown that self-assembly three-dimensional (3D) co-cultures primarily produce cancer-encapsulated fibrosis or maintain a fibrosis-encapsulated tumor mass for a short period, which is inadequate to replicate the function of fibrosis, particularly as a physical barrier. To address this limitation, a multi-layer spheroid formation method is developed to create a fibrosis-encapsulated tumoroid (FET) structure that maintains structural stability for up to 14 days. FETs exhibited faster tumor growth, higher expression of immunosuppressive cytokines, and equal or greater resistance to anticancer drugs compared to their parental tumoroids. Additionally, FETs serve as a versatile model for traditional cancer research, enabling the study of exosomal miRNA and gene functions, as well as for mechanobiology research when combined with alginate hydrogel. Our findings suggest that the FET represents an advanced model that more accurately mimics solid cancer tissue with peritumoral fibrosis. It may show potential superiority over self-assembly-based 3D co-cultures for cancer research and drug screening, and holds promise for personalized drug selection in cancer treatment.

In the realm of cancer research, the tumor microenvironment (TME) plays a crucial role in tumor initiation and progression, shaped by complex interactions between cancer cells and surrounding non-cancerous cells. Cytokines, as essential immunomodulatory agents, are secreted by various cellular constituents within the TME, including immune cells, cancer-associated fibroblasts, and cancer cells themselves. These cytokines facilitate intricate communication networks that significantly influence tumor initiation, progression, metastasis, and immune suppression. Pyroptosis contributes to TME remodeling by promoting the release of pro-inflammatory cytokines and sustaining chronic inflammation, impacting processes such as immune escape and angiogenesis. However, challenges remain due to the complex interplay among cytokines, pyroptosis, and the TME, along with the dual effects of pyroptosis on cancer progression and therapy-related complications like cytokine release syndrome. Unraveling these complexities could facilitate strategies that balance inflammatory responses while minimizing tissue damage during therapy. This review delves into the complex crosstalk between cytokines, pyroptosis, and the TME, elucidating their contribution to tumor progression and metastasis. By synthesizing emerging therapeutic targets and innovative technologies concerning TME, this review aims to provide novel insights that could enhance treatment outcomes for cancer patients.

While high-grade serous ovarian cancer (HGSC) has proven largely resistant to immunotherapy, sporadic incidents of partial and complete response have been observed in clinical trials and case reports. These observations suggest that a molecular basis for effective immunity may exist within a subpopulation of HGSC. Herein, we developed an algorithm, CONSTRU (Computing Prognostic Marker Dependencies by Successive Testing of Gene-Stratified Subgroups), to facilitate the discovery and characterization of molecular backgrounds of HGSC that confer resistance or susceptibility to protective anti-tumor immunity.

We used CONSTRU to identify genes from tumor expression profiles that influence the prognostic power of an established immune cytolytic activity signature (CYTscore). From the identified genes, we developed a stratification signature (STRATsig) that partitioned patient populations into tertiles that varied markedly by CYTscore prognostic power. The tertile groups were then analyzed for distinguishing biological, clinical and immunological properties using integrative bioinformatics approaches.

Patient survival and molecular measures of immune suppression, evasion and dysfunction varied significantly across STRATsig tertiles in validation cohorts. Tumors comprising STRATsig tertile 1 (S-T1) showed no immune-survival benefit and displayed a hyper-immune suppressed state marked by activation of TGF-β, Wnt/β-catenin and adenosine-mediated immunosuppressive pathways, with concurrent T cell dysfunction, reduced potential for antigen presentation, and enrichment of cancer-associated fibroblasts. By contrast, S-T3 tumors exhibited diminished immunosuppressive signaling, heightened antigen presentation machinery, lowered T cell dysfunction, and a significant CYTscore-survival benefit that correlated with mutational burden in a manner consistent with anti-tumor immunoediting. These tumors also showed elevated activity of DNA damage/repair, cell cycle/proliferation and oxidative phosphorylation, and displayed greater proportions of Th1 CD4 + T cells. In these patients, but not those of S-T1 or S-T2, validated predictors of immunotherapy response were prognostic of longer patient survival. Further analyses showed that STRATsig tertile properties were not explained by known HGSC molecular or clinical subtypes or singular immune mechanisms.

STRATsig is a composite of parallel immunoregulatory pathways that mirrors tumor immunogenic potential. Approximately one-third of HGSC cases classify as S-T3 and display a hypo-immunosuppressed and antigenic molecular composition that favors immunologic tumor control. These patients may show heightened responsiveness to current immunotherapies.

Cancer-associated fibroblasts (CAFs) play a key role in cancer progression and treatment outcome. This study dissects the intra-tumoral diversity of CAFs in basal cell carcinoma, squamous cell carcinoma, and melanoma using molecular and spatial single-cell analysis. We identify three distinct CAF subtypes: myofibroblast-like RGS5+ CAFs, matrix CAFs (mCAFs), and immunomodulatory CAFs (iCAFs). Large-cohort tissue analysis reveals significant shifts in CAF subtype patterns with increasing malignancy. Two CAF subtypes exhibit immunomodulatory properties via different mechanisms. mCAFs sythesize extracellular matrix and may restrict T cell invasion in low-grade tumors via ensheathing tumor nests, while iCAFs are enriched in late-stage tumors, and express high levels of cytokines and chemokines to aid immune cell recruitment and activation. This is supported by the induction of an iCAF-like phenotype with immunomodulatory functions in primary healthy fibroblasts exposed to skin cancer cell secretomes. Thus, targeting CAF variants holds promise to enhance immunotherapy efficacy in skin cancers.

In recent decades, cancer has posed a challenging obstacle that humans strive to overcome. While phototherapy and immunotherapy are two emerging therapies compared to traditional methods, they each have their advantages and limitations. These limitations include easy metastasis and recurrence, low response rates, and strong side effects. To address these issues, researchers have increasingly focused on combining these two therapies by utilizing a nano-drug delivery system due to its superior targeting effect and high drug loading rate, yielding remarkable results. The combination therapy demonstrates enhanced response efficiency and effectiveness, leading to a preparation that is highly targeted, responsive, and with low recurrence rates. This paper reviews several main mechanisms of anti-tumor effects observed in combination therapy based on the nano-drug delivery system over the last five years. Furthermore, the challenges and future prospects of this combination therapy are also discussed.

Hypoxia is one of the defining characteristics of the tumor microenvironment (TME) in solid cancers. It has a major impact on the growth and spread of malignant cells as well as their resistance to common treatments like radiation and chemotherapy. Here, we explore the complex functions of hypoxia in the TME and investigate its effects on angiogenesis, immunological evasion, and cancer cell metabolism. For prognostic and therapeutic reasons, hypoxia identification is critical, and recent developments in imaging and molecular methods have enhanced our capacity to precisely locate underoxygenated areas inside tumors. Furthermore, targeted therapies that take advantage of hypoxia provide a potential new direction in the treatment of cancer. Therapeutic approaches that specifically target hypoxic conditions in tumors without causing adverse effects are being led by hypoxia-targeted nanocarriers and hypoxia-activated prodrugs (HAPs). This review provides an extensive overview of this dynamic and clinically significant area of oncology research by synthesizing current knowledge about the mechanisms of hypoxia in cancer, highlighting state-of-the-art detection methodologies, and assessing the potential and efficacy of hypoxia-targeted therapies.

Chronic inflammation poses challenges to effective cancer treatment. Although anti-inflammatory therapies have shown short-term benefits, their long-term implications may be unfavorable because they fail to initiate the necessary inflammatory responses. Recent research underscores the promise of specialized pro-resolving mediators, which play a role in modulating the cancer microenvironment by promoting the resolution of initiated inflammatory processes and restoring tissue hemostasis. This review addresses current insights into how inflammation contributes to cancer pathogenesis and explores recent strategies to resolve inflammation associated with cancer.

Prostate cancer (PCa), the most commonly diagnosed cancer in men worldwide, is particularly challenging for oncologists when a precise prognosis needs to be established. Indeed, the entire clinical management in PCa has important drawbacks, generating an intense debate concerning the possibility to individuate molecular biomarkers able to avoid overtreatment in patients with pathological indolent cancers. To date, the paradigmatic change in the view of cancer pathogenesis prompts to look for prognostic biomarkers not only in cancer epithelial cells but also in the tumor microenvironment. PCa ecology has been defined with increasing details in the last few years, and a number of promising key markers associated with the reactive stroma are now available. Here, we provide an updated description of the most biologically significant and cited prognosis-oriented microenvironment biomarkers derived from the main reactive processes during PCa pathogenesis: tissue adaptations, inflammatory response and metabolic reprogramming. Proposed biomarkers include factors involved in stromal cell differentiation, cancer-normal cell crosstalk, angiogenesis, extracellular matrix remodeling and energy metabolism.

Cancer-associated fibroblasts (CAFs), as key cell populations in the tumor microenvironment (TME), play a crucial role in tumor regulation. Previous studies on a prognostic signature of 8 CAF-related genes in head and neck squamous cell carcinoma (HNSCC) revealed that Secreted frizzled-related protein 1 (SFRP1) is one of the hub genes closely related to CAFs. SFRP1 is deficiently expressed in numerous types of cancer and is classified as a tumor suppressor gene. However, the role of SFRP1 in TME regulation in HNSCC remains unclear. This study aimed to explore the role of SFRP1 in the proliferation and migration of HNSCC cells by mediating CAFs and their regulatory mechanisms.

The expression differences, prognosis, and immune infiltration of SFRP1 in HNSCC were analyzed using the TIMER and GEPIA2 databases. The expression of SFRP1 in HNSCC tumor tissues, as well as the expression and secretion of SFRP1 in CAFs and tumor cells, were examined. An indirect co-culture system was constructed to detect the proliferation, migration, and apoptosis of HNSCC cells, and to clarify the effect of SFRP1 on tumor cells by mediating CAFs. Furthermore, the expression and secretion of 10 cytokines derived from CAFs that act on immune cells were verified.

SFRP1 was differently expressed in HNSCC tumor tissues and highly expressed in CAFs. SFRP1 inhibited the proliferation and migration of tumor cells and promoted apoptosis by mediating CAFs. The detection of CAFs-derived factors suggested that the mechanism of action of SFRP1 was associated with the regulation of immune cells.

SFRP1 inhibits the proliferation and migration of HNSCC cells by mediating CAFs, and the mechanism of action is related to the regulation of immune cells, which may provide new research directions and therapeutic targets for HNSCC.

Neutrophil extracellular trap (NET) is associated with host response, tumorigenesis, and immune dysfunction. However, the link between NET and the tumor microenvironment (TME) of gastric cancer (GC) remains unclear. Our study aims to characterize the expression patterns of NET-related genes and their relationships with clinicopathological characteristics, prognosis, TME features, and immunotherapy efficacy in GC cohorts.

Transcriptomic and single-cell RNA sequencing profiles of GC with annotated clinicopathological data were obtained from TCGA-STAD (n = 415), GSE62254 (n = 300), GSE15459 (n = 192), and GSE183904 (n = 26). The consensus cluster algorithm was used to classify tumor samples into different NET-related clusters. A NET-related signature was constructed using LASSO regression and verified in four immunotherapy cohorts. ROC and Kaplan-Meier analyses were conducted to evaluate the predictive and prognostic value of the model for immunotherapy efficacy.

This study identified two NET-related clusters with distinct clinicopathological features, prognosis, and TME landscapes. The high NET-related cluster, characterized by increased NET-related gene expression, exhibited more aggressive behavior and a worse prognosis (HR = 1.63, P = 0.004) than the low NET-related cluster. DEGs were primarily involved in the chemokine/cytokine-associated pathways. Moreover, the high NET-related cluster had significantly higher levels of TME scores, immune infiltration, and immune effectors (all P < 0.001). The NET-related signature displayed a high predictive accuracy for immunotherapy response (AUC = 0.939, P < 0.001). Furthermore, patients with high NET-related scores consistently harbored a more favorable prognosis in different immunotherapy cohorts (all P < 0.05).

This study identified the NET-related signature as a robust model for predicting immunotherapy response in GC, which can help clinicians make appropriate immunotherapy decisions.

The current study was conducted to explore the impact of macrophages and programmed cell death protein 1 (PD-1) expression on tumor-infiltrating lymphocytes (TILs) on treatment outcomes and to define the interaction between these factors and the clinicopathologic features of advanced cholangiocarcinoma (CCA) patients.

Twenty-five patients with metastatic CCA were recruited for the current study from El-Rajhi Hospital and the Clinical Oncology Department of Assiut University. Additionally, 19 healthy controls were included. Before the flow cytometric detection of immune cells, the diagnosis and staging of CCA were performed based on surgical intervention, imaging, carbohydrate antigen 19-9 (CA19-9), and carcinoembryonic antigen (CEA) determinations. This was followed by flow cytometric detection of CD4+, CD8+, CD4+PD-1+, CD8+PD-1+, and CD11b+CD68+ macrophages in the peripheral blood of both patients and controls.

The current results revealed higher levels of CD4+, CD8+, and CD11b+CD68+ macrophages in controls compared to patients. At the same time, PD-1 expression was significantly higher in patients compared to controls. CD4+ was correlated with improved progression-free survival (PFS), while CD8+PD-1 was associated with shorter PFS. In general, CD4+ and CD8+ levels progressively increased with improved response to treatments, differentiation, single organ site metastasis, and surgical interventions. On the contrary, PD-1 expression and macrophages progressively increased with worsening response, dedifferentiation, multiple organ sites, and surgical interventions. The median PFS was 12 months, and the mean ± standard error (SE) was 13.1 ± 1.3.

CCA has a desmoplastic microenvironment with complex immunologic topography and tumor-reactive stroma. The immune landscape of the peripheral blood mononuclear cells (PBMCs) in CCA patients before treatment could reflect the state of systemic immune function and response to treatments. Our results revealed that T-lymphocytes correlated with better prognosis while macrophages and PD-1+ expression were associated with poor outcomes.

Alterations in the tumor microenvironment are closely associated with the metabolic phenotype of tumor cells. Cancer-associated fibroblasts (CAFs) play a pivotal role in tumor growth and metastasis. Existing studies have suggested that lactate produced by tumor cells can activate CAFs, yet the precise underlying mechanisms remain largely unexplored. In this study, we initially identified that lactate derived from lung cancer cells can promote nuclear translocation of NUSAP1, subsequently leading to the recruitment of the transcriptional complex JUNB-FRA1-FRA2 near the DESMIN promoter and facilitating DESMIN transcriptional activation, thereby promoting CAFs' activation. Moreover, DESMIN-positive CAFs, in turn, secrete IL-8, which recruits TAMs or promotes M2 polarization of macrophages, further contributing to the alterations in the tumor microenvironment and facilitating lung cancer progression. Furthermore, we observed that the use of IL-8 receptor antagonists, SB225002, or Navarixin, significantly reduced TAM infiltration and enhanced the therapeutic efficacy of anti-PD-1 or anti-PD-L1 treatment. This finding indicates that inhibiting IL-8R activity can attenuate the impact of CAFs on the tumor microenvironment, thus restraining the progression of lung cancer.

Liver cancer, which most commonly manifests as hepatocellular carcinoma (HCC), is the sixth most common cancer in the world. In HCC, the immune system plays a crucial role in the growth and proliferation of tumor cells. HCC achieve immune escape through the tumor microenvironment, which significantly promotes the development of this cancer. Here, this article introduces and summarizes the functions and effects of regulatory T cells (Tregs) in the tumor microenvironment, highlighting how Tregs inhibit and regulate the functions of immune and tumor cells, cytokines, ligands and receptors, etc, thereby promoting tumor immune escape. In addition, it discusses the mechanism of CAR-T therapy for HCC and elaborate on the relationship between CAR-T and Tregs.

Fibroblast activation protein (FAP) has attracted considerable attention as a possible target for the radiotherapy of solid tumors. Unfortunately, initial efforts to treat solid tumors with FAP-targeted radionuclides have yielded only modest clinical responses, suggesting that further improvements in the molecular design of FAP-targeted radiopharmaceutical therapies (RPT) are warranted. In this study, we report several advances on the previously described FAP6 radioligand that increase tumor retention and accelerate healthy tissue clearance. Seven FAP6 derivatives with different linkers or albumin binders were synthesized, radiolabeled, and investigated for their effects on binding and cellular uptake. The radioligands were then characterized in 4T1 tumor-bearing Balb/c mice using both single-photon emission computed tomography (SPECT) and ex vivo biodistribution analyses to identify the conjugate with the best tumor retention and tumor-to-healthy organ ratios. The results reveal an optimized FAP6 radioligand that exhibits efficacy and safety properties that potentially justify its translation into the clinic.

Gut Akkermansia muciniphila (Akk) has been implicated in impacting immunotherapy or oncogenesis. This study aims to dissect the Akk-associated tumor immune ecosystem (TIME) by single-cell profiling coupled with T cell receptor (TCR) sequencing. We adopted mouse cancer models under anti-PD-1 immunotherapy, combined with oral administration of three forms of Akk, including live Akk, pasteurized Akk (Akk-past), or its membrane protein Amuc_1100 (Amuc). We show that live Akk is most effective in activation of CD8 T cells by rescuing the exhausted type into cytotoxic subpopulations. Remarkably, only live Akk activates MHC-II-pDC pathways, downregulates CXCL3 in Bgn(+)Dcn(+) cancer-associated fibroblasts (CAFs), blunts crosstalk between Bgn(+)Dcn(+) CAFs and PD-L1(+) neutrophils by a CXCL3-PD-L1 axis, and further suppresses the crosstalk between PD-L1(+) neutrophils and CD8 T cells, leading to the rescue of exhausted CD8 T cells. Together, this comprehensive picture of the tumor ecosystem provides deeper insights into immune mechanisms associated with gut Akk-dependent anti-PD-1 immunotherapy.

Cancer-associated fibroblasts (CAFs) have emerged as a dominant non-hematopoietic cell population in the tumour microenvironment, serving diverse functions in tumour progression. However, the mechanisms via which CAFs influence the anti-tumour immunity remain poorly understood. Here, using multiple tumour models and biopsies from cancer patients, we report that α-SMA+ CAFs can form immunological synapses with Foxp3+ regulatory T cells (Tregs) in tumours. Notably, α-SMA+ CAFs can phagocytose and process tumour antigens and exhibit a tolerogenic phenotype which instructs movement arrest, activation and proliferation in Tregs in an antigen-specific manner. Moreover, α-SMA+ CAFs display double-membrane structures resembling autophagosomes in their cytoplasm. Single-cell transcriptomic data showed an enrichment in autophagy and antigen processing/presentation pathways in α-SMA-expressing CAF clusters. Conditional knockout of Atg5 in α-SMA+ CAFs promoted inflammatory re-programming in CAFs, reduced Treg cell infiltration and attenuated tumour development. Overall, our findings reveal an immunosuppressive mechanism entailing the formation of synapses between α-SMA+ CAFs and Tregs in an autophagy-dependent manner.

Cancer-associated fibroblasts (CAFs) are the major cellular component of the tumor microenvironment and are known to affect tumor growth and response to various treatments. This study was undertaken to investigate the crosstalk between tumor-matched or unmatched CAFs and head and neck squamous cell carcinoma (HNSCC) cells regarding tumor growth and treatment response.

Three HNSCC cell lines (LK0412, LK0902 and LK0923), were cocultured in 2D or in 3D with their tumor-matched CAFs, site matched CAFs from other tumors or normal oral fibroblasts (NOFs). Cell proliferation was assessed as the amount of Ki67 positive cells/ spheroid area in formalin-fixed- paraffin-embedded 3D spheroids stained with Ki67 antibody. Viability after seven days of cisplatin treatment was measured with CellTiter-Glo 3D Viability Assay. The mRNA expression of CAF-associated markers (ACTA2, COL1A2, FAP, PDGFRα, PDGFRβ, PDPN, POSTN and S100A4) in CAFs before and after coculture with tumor cells as well as mRNA expression of CAF-induced genes (MMP1, MMP9 and FMOD) in tumor cells separated from CAFs after co-culture was measured with RT-qPCR. The expression of selected protein biomarkers was validated with immunohistochemistry based on previous mRNA expression results.

The proliferation of the LK0412 and LK0902 tumor spheroids varied significantly when cocultured with different CAFs and NOFs as shown by Ki-67 positive cells. RT‒qPCR analysis revealed different molecular profile of the analyzed HNSCC-derived CAFs concerning the expression of CAF-associated markers. The interaction between CAFs and HNSCC cells was more pronounced after coculture with unmatched CAFs as shown by changes in mRNA expression pattern of CAF-specific markers. Additionally, the unmatched CAFs significantly upregulated the mRNA expression of MMP1, MMP9 and FMOD in tumor cells compared to tumor-matched CAFs.

Our results indicate that tumor-matched CAFs are unique for each tumor and affect the proliferation and the gene/protein expression of tumor cells in a distinct manner. The interaction between tumor unmatched CAFs and HNSCC cells in the tumor spheroids is associated with significant changes in the mRNA expression of CAF-specific markers and significant increases in FMOD and MMP9 in tumor cells compared to when cocultured with tumor-matched CAFs. Taken together, our results show how important the selection of CAFs is to get a reliable in vitro model that mimics the patients' tumor.

Anticancer immune surveillance and immunotherapies trigger activation of cytotoxic cytokine signaling, including tumor necrosis factor-α (TNF-α) and TNF-related apoptosis-inducing ligand (TRAIL) pathways. The pro-inflammatory cytokine TNF-α may be secreted by stromal cells, tumor-associated macrophages, and by cancer cells, indicating a prominent role in the tumor microenvironment (TME). However, tumors manage to adapt, escape immune surveillance, and ultimately develop resistance to the cytotoxic effects of TNF-α. The mechanisms by which cancer cells evade host immunity is a central topic of current cancer research. Resistance to TNF-α is mediated by diverse molecular mechanisms, such as mutation or downregulation of TNF/TRAIL receptors, as well as activation of anti-apoptotic enzymes and transcription factors. TNF-α signaling is also mediated by sphingosine kinases (SphK1 and SphK2), which are responsible for synthesis of the growth-stimulating phospholipid, sphingosine-1-phosphate (S1P). Multiple studies have demonstrated the crucial role of S1P and its transmembrane receptors (S1PR) in both the regulation of inflammatory responses and progression of cancer. Considering that the SphK/S1P/S1PR axis mediates cancer resistance, this sphingolipid signaling pathway is of mechanistic significance when considering immunotherapy-resistant malignancies. However, the exact mechanism by which sphingolipids contribute to the evasion of immune surveillance and abrogation of TNF-α-induced apoptosis remains largely unclear. This study reviews mechanisms of TNF-α-resistance in cancer cells, with emphasis on the pro-survival and immunomodulatory effects of sphingolipids. Inhibition of SphK/S1P-linked pro-survival branch may facilitate reactivation of the pro-apoptotic TNF superfamily effects, although the role of SphK/S1P inhibitors in the regulation of the TME and lymphocyte trafficking should be thoroughly assessed in future studies.

The α-tubulin subtype, Tubulin α-1b chain (TUBA1B), has been shown to influence immune cell infiltration, cancer growth, and survival across various malignancies. However, a comprehensive study has not yet been undertaken examining the immunological and predictive effects of TUBA1B in a pan-carcinoma context. Using data from TCGA, GEO, and other databases, we analyzed TUBA1B expression across various carcinoma types using transcriptional profiling, prognostic implications, genetic and epigenetic alterations, methylation patterns, and immunological significance. To validate our findings, we conducted Western blot analysis to assess TUBA1B protein levels in matched breast cancer tissue samples and performed CCK-8 proliferation assay, flow cytometry, transwell invasion, and migration assays to comprehensively examine the functional impact of TUBA1B on breast cancer cells. Our pan-cancer analysis found TUBA1B upregulation across most tumor types, with varying expression patterns in distinct immune and molecular subtypes. High TUBA1B expression was an independent risk factor and associated with poor prognoses in several cancers, including BRCA, KICH, LGG, LUAD, and MESO. TUBA1B also demonstrates moderate to high diagnostic accuracy in most tumor types. Increased m6A methylation levels were observed in the TUBA1B gene, while its promoter region displayed low methylation levels. TUBA1B's expression impacted some cancers by elevating tumor mutation burden, microsatellite instability, neoantigen formation, immune cell infiltration, and the modulation of immune checkpoints. Functional enrichment analysis highlights TUBA1B's involvement in important cellular processes such as the cell cycle, p53 signaling, cell senescence, programmed cell death, and the regulation of immune-related pathways. Moreover, our study reveals higher TUBA1B protein expression in breast cancer tissues compared to adjacent tissues. In vitro experiments confirm that TUBA1B deletion reduces breast cancer cell proliferation, invasion, and migration while increasing apoptosis. In conclusion, our study suggests that TUBA1B could potentially serve as a diagnostic marker for predicting cancer immunological profiles and survival outcomes and shed light on the expression and role of TUBA1B in breast cancer, providing a solid foundation for considering it as a promising therapeutic target for breast cancer patient treatment.

Cancer-associated fibroblasts (CAF) are the most abundant stromal cells in the tumor microenvironment (TME), especially in solid tumors. It has been confirmed that it can not only interact with tumor cells to promote cancer progression and metastasis, but also affect the infiltration and function of immune cells to induce chemotherapy and immunotherapy resistance. So, targeting CAF has been considered an important method in cancer treatment. The rapid development of nanotechnology provides a good perspective to improve the efficiency of targeting CAF. At present, more and more researches have focused on the application of nanoparticles (NPs) in targeting CAF. These studies explored the effects of different types of NPs on CAF and the multifunctional nanomedicines that can eliminate CAF are able to enhance the EPR effect which facilitate the anti-tumor effect of themselves. There also exist amounts of studies focusing on using NPs to inhibit the activation and function of CAF to improve the therapeutic efficacy. The application of NPs targeting CAF needs to be based on an understanding of CAF biology. Therefore, in this review, we first summarized the latest progress of CAF biology, then discussed the types of CAF-targeting NPs and the main strategies in the current. The aim is to elucidate the application of NPs in targeting CAF and provide new insights for engineering nanomedicine to enhance immune response in cancer treatment.

Currently, pancreatic cancer (PC) is one of the most lethal malignant tumors. PC is typically diagnosed at a late stage, exhibits a poor response to conventional treatment, and has a bleak prognosis. Unfortunately, PC's survival rate has not significantly improved since the 1960s. Cancer-associated fibroblasts (CAFs) are a key component of the pancreatic tumor microenvironment (TME). They play a vital role in maintaining the extracellular matrix and facilitating the intricate communication between cancer cells and infiltrated immune cells. Exploring therapeutic approaches targeting CAFs may reverse the current landscape of PC therapy. In recent years, nano-drug delivery systems have evolved rapidly and have been able to accurately target and precisely release drugs with little or no toxicity to the whole body. In this review, we will comprehensively discuss the origin, heterogeneity, potential targets, and recent advances in the nano-drug delivery system of CAFs in PC. We will also propose a novel integrated treatment regimen that utilizes a nano-drug delivery system to target CAFs in PC, combined with radiotherapy and immunotherapy. Additionally, we will address the challenges that this regimen currently faces.