The tumor microenvironment (TME) is a critical determinant of tumor initiation, progression, and therapeutic response, and serves as the basis for designing precise delivery strategies. Its marked heterogeneity underscores the need for a more comprehensive understanding of its composition and function. In addition to the extensively studied classical TME, emerging evidence highlights the significant roles of the tumor mechanical microenvironment and the tumor microbial microenvironment in modulating treatment efficacy. These non-classical dimensions not only independently influence tumor behavior but also interact dynamically with classical TME components. Mechanical cues within the TME, including matrix stiffness and solid stress, significantly affect drug distribution and treatment efficacy, suggesting that mechanical remodeling represents a potential strategy to enhance therapeutic outcomes. Concurrently, tumor-associated microbiota and their metabolites participate in immune regulation and metabolic reprogramming, contributing to tumor development and offering novel therapeutic targets. Moreover, recent advances have broadened our understanding on the multilayered regulatory landscape of the TME through the investigation of previously underappreciated factors such as neural regulation, metabolic niche dynamics, spatiotemporal heterogeneity, and epigenetic modulation. This review systematically summarizes the characteristics of these diverse TME dimensions and highlights recent progress in targeted delivery strategies, to facilitate the development of more personalized and effective anticancer therapies.
Humans ; Tumor Microenvironment ; Neoplasms/pathology* ; Drug Delivery Systems ; Antineoplastic Agents/administration & dosage*

T cell exhaustion plays an immunosuppressive role in malignant tumors. Continuous tumor antigen stimulation, the presence of suppressive immune cells and cytokines in the tumor microenvironment, the up regulation of inhibitory receptor expression on the surface of T cells, changes in T cell related transcription factors, and metabolites in the tumor microenvironment may lead to T cell exhaustion. Reversing the exhaustion of T cells in tumor patients is a promising strategy for tumor immunotherapy. This article will review the latest research progress on T cell exhaustion status, pathogenesis, reversal methods, and clinical applications in hematological tumors.
Humans ; Hematologic Neoplasms/immunology* ; T-Lymphocytes/immunology* ; Tumor Microenvironment ; Immunotherapy ; T-Cell Exhaustion

Extramedullary disease (EMD) is an independent prognostic factor for multiple myeloma (MM). Compared with MM without EMD, MM with EMD has different genetic characteristics, with a higher incidence of high-risk chromosomal abnormalities, more complex genomic profile, and immunophenotypic features related to adhesion molecule and chemokine expression. The mutual regulation between myeloma cells and tumor microenvironment, including changes in immune environment, deposition of extracellular matrix, abnormal expression of adhesion molecules, and autocrine secretion of myeloma cells, is involved in the extramedullary migration of myeloma cells. Various immune-targeted therapies have improved the prognosis of extramedullary MM (EMM). This article reviews the genetic characteristics of EMM, important role of tumor microenvironment, and progress of treatment.
Multiple Myeloma/therapy* ; Prognosis ; Incidence ; Gene Expression Regulation, Neoplastic ; Tumor Microenvironment ; Extracellular Matrix/metabolism* ; Cell Adhesion ; Humans ; Immunophenotyping

This study aimed to investigate the regulatory effect and mechanism of thymopentin on the growth of subcutaneous hepatocellular carcinoma in mice. A subcutaneous tumor model of Hepa1-6 liver cancer in immunocompetent mice was constructed, with three randomly divided groups based on tumor volume: control group, low-dose thymopentin (TP5) group (10 mg/kg), and high-dose TP5 group (20 mg/kg), with 6 mice in each group. Drugs were administered, and the intervention effect of thymopentin on tumor growth was evaluated. Hepa1-6 cells were then cultured in vitro and treated with blank medium and TP5 of different concentrations (10, 100, 1000 ng/mL) for 72 hours. Cell viability was detected by sulforhodamine B (SRB) colorimetry. A subcutaneous tumor model of liver cancer LM3 in immunocompromised mice was constructed, with three randomly divided groups based on tumor volume: control group, TP5 group (20 mg/kg), and positive drug Sorafinib group (30 mg/kg). The intervention effect of thymopentin on the growth of subcutaneous tumors in immunocompromised mice was evaluated. Flow cytometry was used to analyze the changes in the proportion of T cells and myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment 11 days after TP5 administration in the Hepa1-6 model. MDSCs were cultured in vitro and treated with TP5. The effect of TP5 on MDSCs was evaluated by detecting the levels of ROS, IL-6, and NO, which are effector molecules of MDSCs. The mouse subcutaneous liver cancer model was established again using C57BL/6N mice. After 10 days, they were randomly divided into four groups based on tumor volume: control group, low-dose TP5 group (10 mg/kg), high-dose TP5 group (20 mg/kg), and arginine-deficient TP5 group (15 mg/kg). Drugs were administered continuously for 11 days, and the intervention effect of arginine-deficient TP5 on tumor growth was evaluated based on tumor weight. Annexin-V staining was used to detect the impact of TP5 on T cell survival. The results showed that both low and high doses of TP5 inhibited the growth of subcutaneous liver cancer in immunocompetent mice (P < 0.05), yet TP5 had no direct inhibitory effect on the proliferation of tumor cells cultured in vitro. Besides, a high dose of TP5 could not inhibit the growth of subcutaneous liver cancer in immunocompromised mice. Furthermore, TP5 promoted the infiltration of CD4 and CD8 T cells but decreased MDSCs in the subcutaneous tumor microenvironment of immunocompetent mice. TP5 did not affect the levels of ROS, IL-6, and NO in MDSCs. Lastly, arginine-deficient TP5 could not inhibit the growth of subcutaneous liver cancer in immunocompetent mice. Accordingly, TP5 but not arginine-deficient TP5 promoted the increase in the proportion of viable CD4 and CD8 T cells cultured in vitro. These results suggest that TP5 may inhibit the growth of liver cancer by increasing T cell number in the liver cancer microenvironment.
thymopentin ; hepatocellular carcinoma ; tumor microenvironment ; arginine ; T cells

Lung cancer is the malignant tumor with the highest mortality rate worldwide. The tumor microenvironment (TME) is a key factor in the progression of lung cancer, composed of tumor cells, signaling molecules, fibroblasts, immune cells, etc. Among them, tumor associated neutrophil (TAN), as an important component of immune cells in the TME, plays multiple roles in tumor cell proliferation, invasion, angiogenesis, and metastasis due to its aberrant function, and is closely associated with poor prognosis. However, there are limited researches on the mechanism of TAN in lung cancer. This review aims to provide more scientific basis for studying the therapeutic targets of lung cancer and developing new drugs by elucidating the different subtypes of TAN and their mechanisms of action in the occurrence and development of lung cancer.
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Humans ; Neutrophils/pathology* ; Lung Neoplasms/pathology* ; Tumor Microenvironment ; Animals

Lung cancer is one of the most common and lethal malignancies in China. In the context of the tumor microenvironment, neutrophil extracellular traps (NETs) released by neutrophils exert a profound impact on the occurrence and progression of lung cancer. Although the exact mechanisms by which NETs promote tumor growth have not been fully elucidated, existing research has revealed their multiple roles in tumor growth, invasion, metastasis, and cancer-related thrombosis. This article will review the molecular biology mechanisms and research progress of NETs in lung cancer based on recent studies.
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Extracellular Traps/metabolism* ; Humans ; Lung Neoplasms/drug therapy* ; Neutrophils/immunology* ; Animals ; Tumor Microenvironment

Neuroendocrine carcinoma (NEC) represents a category of malignant tumors originating from neuroendocrine cells. Given that NEC cells exhibit characteristics of both neural and endocrine cells, they can hijack neuronal signaling pathways and dynamically regulate the expression of neuronal lineage markers during tumor metastasis, thereby constructing a microenvironment conducive to tumor growth and metastasis. Conversely, alterations in the tumor microenvironment can enhance the interactions between neurons and tumor cells, ultimately synergistically promoting the metastasis of NEC. This review highlights recent advancements in the field of cancer neuroscience, uncovering neuronal lineage markers in NEC that facilitate tumor dissemination through mediating crosstalk, bidirectional communication, and synergistic interactions between tumor cells and the nervous system. Consequently, the latest findings in tumor neuroscience have enriched our understanding of the biological mechanisms underlying tumor metastasis, opening new research avenues for a deeper comprehension of the complex biological processes involved in tumor metastasis, particularly brain metastasis. This review provides a comprehensive review of the crosstalk between tumor cells and neural signaling in the metastasis of NEC.
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Humans ; Carcinoma, Neuroendocrine/metabolism* ; Signal Transduction ; Animals ; Neoplasm Metastasis ; Neurons/pathology* ; Tumor Microenvironment ; Cell Communication

Neutrophil extracellular traps (NETs), intricate reticular structures released by activated neutrophils, play a pivotal regulatory role in the pathogenesis of malignant tumors. Lung cancer is one of the most prevalent malignancies globally, with persistently high incidence and mortality rates. Recent studies have revealed that NETs dynamically modulate the tumor microenvironment through unique pathological mechanisms, exhibiting complex immunoregulatory characteristics during the progression of lung cancer, and this discovery has increasingly become a focal point in tumor immunology research. This paper provides a comprehensive review of the latest advancements in NETs research related to lung cancer, offering an in-depth analysis of their impact on lung cancer progression, their potential diagnostic value, and the current state of research on targeting NETs for lung cancer prevention and treatment. The aim is to propose novel strategies to enhance therapeutic outcomes and improve the prognosis for lung cancer patients.
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Extracellular Traps/immunology* ; Humans ; Lung Neoplasms/metabolism* ; Neutrophils/metabolism* ; Animals ; Tumor Microenvironment

Despite the groundbreaking advances in cancer immunotherapy achieved by immune checkpoint inhibitors (ICIs), their efficacy remains limited by the immunosuppressive tumor microenvironment (TME). Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), key effectors of the Hippo signaling pathway, play pivotal roles in tumor immune evasion. They directly regulate the expression of immune checkpoints, mediate the formation of an immunosuppressive microenvironment, inhibit T cell function, and interact with other signaling pathways to promote immune escape. Diverse strategies targeting YAP/TAZ have been developed, including direct inhibition, modulation of upstream regulators, and suppression of downstream target genes. Preclinical studies have demonstrated that combining YAP/TAZ inhibition with ICIs significantly enhances therapeutic efficacy across various tumor models. This review summarizes recent advances in understanding the role of YAP/TAZ in immune evasion within the TME and explores the potential of targeting this pathway to improve immunotherapy outcomes. Furthermore, it discusses the translational value of combination therapies based on YAP/TAZ inhibition, providing a theoretical framework and practical guidance for the development of innovative immunotherapeutic strategies and precision medicine approaches.
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Humans ; Immunotherapy/methods* ; Neoplasms/metabolism* ; Signal Transduction/drug effects* ; Adaptor Proteins, Signal Transducing/immunology* ; Animals ; Transcriptional Coactivator with PDZ-Binding Motif Proteins ; Transcription Factors/immunology* ; YAP-Signaling Proteins ; Tumor Microenvironment

Immune checkpoint blockade therapy has demonstrated remarkable efficacy in treating various malignancies; however, its clinical application remains challenged by low response rates and immune-related adverse events. Immunoglobulin superfamily member 11 (IGSF11), an inhibitory immune checkpoint molecule, serves as a specific ligand for the V-domain immunoglobulin suppressor of T cell activation (VISTA). Through the IGSF11/VISTA axis, it suppresses T cell function and represents a promising novel target for cancer immunotherapy. IGSF11 is widely expressed across multiple tumor types, though its regulatory mechanisms vary depending on the malignancy. Studies have confirmed that blocking the IGSF11-VISTA interaction or specifically inhibiting IGSF11 exerts antitumor effects. While IGSF11 is closely associated with patient prognosis, its prognostic significance differs among cancer types. This review systematically summarizes the structural characteristics of IGSF11, its regulatory mechanisms, interaction with VISTA, and functional role within the tumor microenvironment.
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Humans ; Immunotherapy ; Neoplasms/metabolism* ; B7 Antigens/chemistry* ; Animals ; Molecular Targeted Therapy ; Tumor Microenvironment