Gliomas are the most common primary neuroepithelial tumors of the central nervous system in adults, of which glioblastoma is the deadliest subtype. Apart from the intrinsically indestructible characteristics of glioma (stem) cells, accumulating evidence suggests that the tumor microenvironment also plays a vital role in the refractoriness of glioblastoma. The primary functions of platelets are to stop bleeding and regulate thrombosis under physiological conditions. Furthermore, platelets are also active elements that participate in a variety of processes of tumor development, including tumor growth, invasion, and chemoresistance. Glioma cells recruit and activate resting platelets to become tumor-educated platelets (TEPs), which in turn can promote the proliferation, invasion, stemness, and chemoresistance of glioma cells. TEPs can be used to obtain genetic information about gliomas, which is helpful for early diagnosis and monitoring of therapeutic effects. Platelet membranes are intriguing biomimetic materials for developing efficacious drug carriers to enhance antiglioma activity. Herein, we review the recent research referring to the contribution of platelets to the malignant characteristics of gliomas and focusing on the molecular mechanisms mediating the interaction between TEPs and glioma (stem) cells, as well as present the challenges and opportunities in targeting platelets for glioma therapy.
Humans ; Glioma/metabolism* ; Blood Platelets/physiology* ; Brain Neoplasms/pathology* ; Tumor Microenvironment

Colorectal cancer (CRC), a major global health concern, necessitates innovative treatments. Chimeric antigen receptor (CAR) T cells have shown promises, yet they grapple with challenges. The spotlight pivots to the rising heroes: CAR natural killer (NK) cells, offering advantages such as higher safety profiles, cost-effectiveness, and efficacy against solid tumors. Nevertheless, the specific mechanisms underlying CAR NK cell trafficking and their interplay within the complex tumor microenvironment require further in-depth exploration. Herein, we provide insights into the design and engineering of CAR NK cells, antigen targets in CRC, and success in overcoming resistance mechanisms with an emphasis on the potential for clinical trials.
Colorectal Neoplasms/immunology* ; Humans ; Killer Cells, Natural/metabolism* ; Receptors, Chimeric Antigen/genetics* ; Immunotherapy, Adoptive/methods* ; Tumor Microenvironment/immunology* ; Animals

Lung cancer is one of the most lethal tumors in the world with a 5-year overall survival rate of less than 20%, mainly including lung adenocarcinoma (LUAD). Tumor microenvironment (TME) has become a new research focus in the treatment of lung cancer. The TME is heterogeneous in composition and consists of cellular components, growth factors, proteases, and extracellular matrix. The various cellular components exert a different role in apoptosis, metastasis, or proliferation of lung cancer cells through different pathways, thus contributing to the treatment of adenocarcinoma and potentially facilitating novel therapeutic methods. This review summarizes the research progress on different cellular components with cell-cell interactions in the TME of LUAD, along with their corresponding drug candidates, suggesting that targeting cellular components in the TME of LUAD holds great promise for future theraputic development.
Humans ; Tumor Microenvironment/drug effects* ; Adenocarcinoma of Lung/drug therapy* ; Lung Neoplasms/pathology* ; Adenocarcinoma/metabolism* ; Animals ; Apoptosis/physiology*

In recent years, growing evidence indicates that the nervous system plays an indispensable role in tumor development and metastasis. Elucidating crosstalk between the nervous system and tumor progression has thrived as a hot topic and a new direction for understanding cancer pathogenesis. Notably, many novel discoveries have suggested that neurotransmitter receptors (NRs) are not only widely expressed in cancer cells, but also play key roles in regulating cancer initiation and progression by diverse approaches. In this review, we summarized the latest advance in cancer neuroscience, especially emphasizing the important roles of different NRs in cancer development and prevention. The exemplary studies presented herein illustrate the emerging view that NRs are profoundly influential, manifested in tumor growth, apoptosis, angiogenesis, metastasis, resistance to drugs, and participate in the formation of neural-cancer interactions. In addition, NRs also regulate cellular metabolic processes and tumor microenvironment (TME) remodeling. More importantly, numerous basic and clinical studies have suggested that NRs may be potential targets for cancer treatments, and corresponding agonists or antagonists have been identified effectively in controlling tumor growth and metastasis. In conclusion, NRs are emerging as novel targets for anti-cancer drug exploration and clinical cancer treatments, while trying to uncover deeper mechanisms and connections between NRs and cancer is of high clinical significance and translational value.
Humans ; Neoplasms/metabolism* ; Receptors, Neurotransmitter/physiology* ; Animals ; Tumor Microenvironment/physiology*

BACKGROUND: Several studies have demonstrated the occurrence of secondary tumors as a rare but significant complication of chimeric antigen receptor T (CAR-T) cell therapy, underscoring the need for a detailed investigation. Given the limited variety of secondary tumor types reported to date, a comprehensive characterization of the various secondary tumors arising after CAR-T therapy is essential to understand the associated risks and to define the role of the immune microenvironment in malignant transformation. This study aims to characterize the immune microenvironment of a newly identified secondary tumor post-CAR-T therapy, to clarify its pathogenesis and potential therapeutic targets. METHODS: In this study, the bone marrow (BM) samples were collected by aspiration from the primary and secondary tumors before and after CD19 CAR-T treatment. The CD45 + BM cells were enriched with human CD45 microbeads. The CD45 + cells were then sent for 10× genomics single-cell RNA sequencing (scRNA-seq) to identify cell populations. The Cell Ranger pipeline and CellChat were used for detailed analysis. RESULTS: In this study, a rare type of secondary chronic myelomonocytic leukemia (CMML) were reported in a patient with diffuse large B-cell lymphoma (DLBCL) who had previously received CD19 CAR-T therapy. The scRNA-seq analysis revealed increased inflammatory cytokines, chemokines, and an immunosuppressive state of monocytes/macrophages, which may impair cytotoxic activity in both T and natural killer (NK) cells in secondary CMML before treatment. In contrast, their cytotoxicity was restored in secondary CMML after treatment. CONCLUSIONS This finding delineates a previously unrecognized type of secondary tumor, CMML, after CAR-T therapy and provide a framework for defining the immune microenvironment of secondary tumor occurrence after CAR-T therapy. In addition, the results provide a rationale for targeting macrophages to improve treatment strategies for CMML treatment.
Humans ; Lymphoma, Large B-Cell, Diffuse/therapy* ; Tumor Microenvironment/genetics* ; Antigens, CD19/metabolism* ; Leukemia, Myelomonocytic, Chronic/genetics* ; Immunotherapy, Adoptive/adverse effects* ; Male ; Single-Cell Analysis/methods* ; Female ; Sequence Analysis, RNA/methods* ; Receptors, Chimeric Antigen ; Middle Aged

BACKGROUND: Cervical squamous cell carcinoma (CESC), the most common subtype of cervical cancer, is primarily caused by the high-risk human papillomavirus (HPV) infection and genetic susceptibility. Single-cell RNA sequencing (scRNA-seq) has been widely used in CESC research to uncover the diversity of cell types and states within tumor tissues, enabling a detailed study of the tumor microenvironment (TME). This technology allows precise mapping of HPV infection in cervical tissues, providing valuable insights into the initiation and progression of HPV-mediated malignant transformation. METHODS: We performed the scRNA-seq to characterize gene expression in tumor tissues and paired adjacent para-cancerous tissues from four patients with early-stage CESC using the 10× Genomics platform. The HPV infection and its subtypes were identified using the scRNA data and viral sequence mapping, and trajectory analyses were performed using HPV+ or HPV- cells. Interactions between different types of keratinized cells and their interactions with other cell types were identified, and pathways and specificity markers were screened for proliferating keratinized cells. The Cancer Genome Atlas (TCGA) dataset was used to verify the prognostic correlation between tumor-specific PI3+S100A7+ keratinocyte infiltration and CESC, and the localization relationship between PI3+S100A7+ keratinocytes and macrophages was verified by immunofluorescence staining. RESULTS: Various types of keratinocytes and fibroblasts were the two cell types with the most significant differences in percentage between the tumor tissue samples and paired adjacent non-cancerous tissue samples in the early stages of CESC. We found that PI3+S100A7+ keratinocytes were associated with early HPV-positive CESC, and PI3+S100A7+ keratinocytes were more abundant in tumors than in adjacent normal tissues in the TCGA-CESC dataset. Analysis of clinical information revealed that the infiltration of PI3+S100A7+ keratinocytes was notably higher in tumors with poor prognosis than in those with good prognosis. Additionally, multiplex immunofluorescence analysis showed a specific increase in PI3+S100A7+ expression within tumor tissues, with PI3+S100A7+ keratinocytes and CD163+ macrophages being spatially very close to each other. In the analysis of cell-cell interactions, macrophages exhibited strong crosstalk with PI3+S100A7+ proliferating keratinocytes in HPV-positive CESC tumors, mediated by tumor necrosis factor (TNF), CCL2, CXCL8, and IL10, highlighting the dynamic and tumor-specific enhancement of macrophage-keratinocyte interactions, which are associated with poor prognosis and immune modulation. Using CIBERSORTx, we discovered that patients with high infiltration of both PI3+S100A7+ proliferating keratinocytes and macrophages had the shortest overall survival. In the analysis of cell-cell interactions, PI3+S100A7+ proliferating keratinocytes and macrophages were found to be involved in highly active pathways that promote differentiation and structure formation, including cytokine receptor interactions, the Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway, and TNF signaling pathway regulation. Further subtyping of fibroblast populations identified four subtypes. The C1 group, characterized by its predominance in tumor tissues, is a subtype enriched with cancer-associated fibroblasts (CAFs), whereas the C3 group is primarily enriched in adjacent non-cancerous tissues and consists of undifferentiated cells. Moreover, the distinct molecular and cellular differences between HPV16- and HPV66-associated tumors were demonstrated, emphasizing the unique tumor-promoting mechanisms and microenvironmental influences driven by each HPV subtype. CONCLUSIONS We discovered a heterogeneous population of keratinocytes between tumor and adjacent non-cancerous tissues caused by HPV infection and identified macrophages and specific CAFs that play a crucial role during the early stage in promoting the inflammatory response and remodeling the cancer-promoting TME. Our findings provide new insights into the transcriptional landscape of early-stage CESC to understand the mechanism of HPV-mediated malignant transformation in cervical cancer.
Humans ; Female ; Papillomavirus Infections/genetics* ; Uterine Cervical Neoplasms/genetics* ; Carcinoma, Squamous Cell/pathology* ; Keratinocytes/metabolism* ; Single-Cell Analysis/methods* ; Tumor Microenvironment/genetics*

Metal ion-promoted chemodynamic therapy(CDT) combined with photodynamic therapy(PDT) offers broad application prospects for enhancing anti-tumor effects. In this study, glycyrrhizic acid(GA), copper ions(Cu~(2+)), and norcantharidin(NCTD) were co-assembled to successfully prepare a natural small-molecule, carrier-free hydrogel(NCTD Gel) with excellent material properties. Under 808 nm laser irradiation, NCTD Gel responded to the tumor microenvironment(TME) and acted as an efficient Fenton reagent and photosensitizer, catalyzing the conversion of endogenous hydrogen peroxide(H_2O_2) within the tumor into oxygen(O_2), and hydroxyl radicals(·OH, type Ⅰ reactive oxygen species) and singlet oxygen(~1O_2, type Ⅱ reactive oxygen species), while depleting glutathione(GSH) to stabilize reactive oxygen species and alleviate tumor hypoxia. In vitro and in vivo experiments demonstrated that NCTD Gel exhibited significant CDT/PDT synergistic therapeutic effects. Further safety evaluation and metabolic testing confirmed its good biocompatibility and safety. This novel hydrogel is not only simple to prepare, safe, and cost-effective but also holds great potential for clinical transformation, providing insights and references for the research and development of metal ion-mediated hydrogel-based anti-tumor therapies.
Hydrogels/chemistry* ; Animals ; Photochemotherapy ; Humans ; Mice ; Antineoplastic Agents/administration & dosage* ; Photosensitizing Agents/chemistry* ; Neoplasms/metabolism* ; Female ; Copper/chemistry* ; Reactive Oxygen Species/metabolism* ; Tumor Microenvironment/drug effects* ; Cell Line, Tumor ; Male

The tumor microenvironment is a crucial factor in tumor occurrence and progression. The hypoxic microenvironment is widely present in tumor tissue and is a key endogenous factor accelerating tumor deterioration. The "blood stasis toxin" theory, as an emerging perspective in tumor research, is regarded as the unique "soil" in tumor progression from the perspective of traditional Chinese medicine(TCM) due to its dynamic evolution mechanism, which closely resembles the formation of the hypoxic microenvironment. Scientifically integrating TCM theories with the biological characteristics of tumors and exploring precise syndrome differentiation and treatment strategies are key to achieving comprehensive tumor prevention and control. This article focused on the hypoxic microenvironment of the tumor, elucidating its formation mechanisms and evolutionary processes and carefully analyzing the internal relationship between the "blood stasis toxin" theory and the hypoxic microenvironment. Additionally, it explored the interaction among blood stasis, toxic pathogens, and hypoxic environment and proposed micro-level prevention and treatment strategies targeting the hypoxic microenvironment based on the "blood stasis toxin" theory, aiming to provide TCM-based theoretical support and therapeutic approaches for precise regulation of the hypoxic microenvironment.
Humans ; Tumor Microenvironment/drug effects* ; Neoplasms/therapy* ; Animals ; Medicine, Chinese Traditional ; Disease Progression ; Drugs, Chinese Herbal

Non-small cell lung cancer(NSCLC) is the most common type of lung cancer worldwide, accounting for approximately 80%-85% of all lung cancer cases. Despite the clinical benefits of traditional treatments such as surgery, chemotherapy, and radiotherapy, challenges such as the high rate of postoperative recurrence and resistance of some patients to chemotherapy and targeted therapies limit their effectiveness, necessitating the exploration of more effective treatment options. In recent years, immunotherapy, especially immune checkpoint inhibitors(ICIs), has revolutionized NSCLC treatment and significantly improved the survival prognosis of some patients. However, the efficacy of immunotherapy is limited by tumor immune escape, drug resistance, and immune-related adverse events(irAEs), which have not been effectively addressed. Traditional Chinese medicine(TCM), as a traditional therapeutic approach, has shown unique advantages in NSCLC treatment, with studies indicating its ability to enhance immune responses, regulate immune checkpoints, and improve the tumor microenvironment(TME), thus boosting the efficacy of immunotherapy. Additionally, the multi-target and multi-pathway effects of TCM help mitigate the side effects of immunotherapy, further improving efficacy and safety. This review summarizes the latest research progress of TCM in NSCLC immunotherapy, focusing on the research results of TCM in enhancing the effect of immunotherapy by regulating immune cells, optimizing the immune microenvironment, and being applied with ICIs, etc. The latest research progress of TCM in alleviating irAEs is also elucidated. The aim is to provide theoretical support for the clinical application of TCM in the prevention and treatment of NSCLC and the research and development of new drugs and promote the optimization and development of combined immunotherapy and TCM treatment models.
Humans ; Carcinoma, Non-Small-Cell Lung/therapy* ; Lung Neoplasms/therapy* ; Immunotherapy/methods* ; Drugs, Chinese Herbal/therapeutic use* ; Medicine, Chinese Traditional ; Animals ; Tumor Microenvironment/drug effects*

Objective To explore the clinical and immunological significance of CCDC97 in hepatocellular carcinoma (HCC). Methods Clinical data and RNA sequencing results from HCC patients were retrieved from TCGA and ICGC databases. Bioinformatics analysis and in vitro experiments were performed to investigate the role of CCDC97 in HCC. Results The expression level of CCDC97 was elevated in HCC patients and HCC cells, closely associated with pathological features and prognosis. CCDC97 was identified as a novel prognostic biomarker. It is linked to the spliceosome pathway, which is significantly active in tumors and potentially promotes carcinogenesis. CCDC97 is also highly expressed in various immune cells and is associated with microenvironment. Furthermore, knocking down CCDC97 in vitro suppressed cell migration, invasion, and proliferation. Conclusion CCDC97 plays a critical role in HCC progression and the immune microenvironment, making it a potential target for prognosis and therapeutic intervention.
Humans ; Carcinoma, Hepatocellular/metabolism* ; Liver Neoplasms/metabolism* ; Tumor Microenvironment/genetics* ; Cell Movement/genetics* ; Cell Proliferation ; Prognosis ; Cell Line, Tumor ; Gene Expression Regulation, Neoplastic ; Biomarkers, Tumor/genetics* ; Male