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*

Microwave thermochemotherapy (MTC) has been applied to treat lip squamous cell carcinoma (LSCC), but a deeper understanding of its therapeutic mechanisms and molecular biology is needed. To address this, we used single-cell transcriptomics (scRNA-seq) and spatial transcriptomics (ST) to highlight the pivotal role of tumor-associated neutrophils (TANs) among tumor-infiltrating immune cells and their therapeutic response to MTC. MNDA⁺ TANs with anti-tumor activity (N1-phenotype) are found to be abundantly infiltrated by MTC with benefit of increased blood perfusion, and these TANs are characterized by enhanced cytotoxicity, ameliorated hypoxia, and upregulated IL1B, activating T&NK cells and fibroblasts via IL1B-IL1R. In this highly anti-tumor immunogenic and hypoxia-reversed microenvironment under MTC, fibroblasts accumulated in the tumor front (TF) can recruit N1-TANs via CXCL2-CXCR2 and clear N2-TANs (pro-tumor phenotype) via CXCL12-CXCR4, which results in the aggregation of N1-TANs and extracellular matrix (ECM) deposition. In addition, we construct an N1-TANs marker, MX2, which positively correlates with better prognosis in LSCC patients, and employ deep learning techniques to predict expression of MX2 from hematoxylin-eosin (H&E)-stained images so as to conveniently guide decision making in clinical practice. Collectively, our findings demonstrate that the N1-TANs/fibroblasts defense wall formed in response to MTC effectively combat LSCC.
Humans ; Neutrophils/metabolism* ; Single-Cell Analysis ; Lip Neoplasms/genetics* ; Hyperthermia, Induced/methods* ; Microwaves/therapeutic use* ; Transcriptome ; Carcinoma, Squamous Cell/immunology* ; Tumor Microenvironment

In the ever-evolving landscape of cancer therapy, while cancer treatments such as chemotherapy, radiotherapy, and targeted therapy aim to eradicate malignant cells, they also inadvertently trigger cellular senescence in both cancerous and microenvironmental tissues. Therapy-induced senescence (TIS) can act as a barrier against tumor growth by halting cell proliferation in the short term, but the long-term persistence of therapy-induced senescent (TISnt) cells may pose a significant challenge in cancer management. Their distinct characteristics, like senescence-associated secretory phenotype (SASP), metabolic dysregulation, and immune evasion, make them exhibit remarkable heterogeneity to orchestrate the tumor microenvironment (TME), resulting in therapy resistance. However, how these TISnt cells functioning differently in cancer progression, and the intricate mechanisms by which they remodel the senescence-associated immunosuppressive microenvironment present challenges for improving anticancer therapy. Therefore, this review summarizes the heterogeneous TISnt cell phenotypes contributing to an accumulated senescent state, outlines their multidimensional interactions in the senescent microenvironment, and discusses current senescence-targeting strategies. Building on the current understanding of TIS, we propose potential avenues for improving TIS-targeting methodologies in the context of head and neck cancer, a representative heterogeneous malignancy, which can substantially enhance the efficacy of the "one-two punch" sequential treatment approach for head and neck cancer.
Humans ; Cellular Senescence/drug effects* ; Tumor Microenvironment ; Neoplasms/pathology* ; Senescence-Associated Secretory Phenotype

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

Lactic acid (LA) accumulation in tumor microenvironments (TME) has been implicated in immune suppression and tumor progress. Diverse roles of LA have been elucidated, including microenvironmental pH regulation, signal transduction, post-translational modification, and metabolic remodeling. This review summarizes LA functions within TME, focusing on the effects on tumor cells, immune cells, and stromal cells. Reducing LA levels is a potential strategy to attack cancer, which inevitably affects the physiological functions of normal tissues. Alternatively, transporting LA into the mitochondria as an energy source for immune cells is intriguing. We underscore the significance of LA in both tumor biology and immunology, proposing the burning of LA as a potential therapeutic approach to enhance antitumor immune responses.
Humans ; Tumor Microenvironment/immunology* ; Neoplasms/therapy* ; Lactic Acid/immunology* ; Mitochondria/metabolism* ; Animals ; Signal Transduction

The Warburg effect, originally discovered by Otto Warburg, refers to the metabolic reprogramming of tumor cells from aerobic oxidation to glycolysis, enabling rapid energy production to support their growth and metastasis. This process is accompanied by the massive production and accumulation of lactate both intracellularly and extracellularly. The resulting acidic microenvironment impairs the normal physiological functions of immune cells and promotes tumor progression. An increasing number of studies indicate that lactate, a key metabolite in the tumor microenvironment (TME), acts as a pivotal immunosuppressive signaling molecule that modulates immune cell function. This review aims to comprehensively examine lactate's role as an immunosuppressive molecule in TME. It focuses on mechanisms such as membrane receptor binding, functional reshaping of immune cells via lactate shuttle transport, epigenetic regulation of gene expression through histone lactylation, and modulation of protein structure and function through nonhistone lactylation, emphasizing lactate's importance in immune regulation within the TME. Ultimately, this review offers novel insights into immunosuppressive therapies aimed at targeting lactate function.
Humans ; Neoplasms/metabolism* ; Tumor Microenvironment/immunology* ; Lactic Acid/immunology* ; Warburg Effect, Oncologic ; Animals ; Glycolysis ; Epigenesis, Genetic

The introduction of PD-1 blockades to chemotherapy and radiotherapy has shown promising outcomes in patients with nasopharyngeal carcinoma, but anti-PD-1 therapies are only effective in a small proportion of patients, indicating the need for reliable predictive biomarkers of benefit from immunotherapy. Here, we summarized recent advances in immunotherapy for nasopharyngeal carcinoma and studies on potential predictors that correlated with treatment response or long-term survival after immunotherapy, including biomarkers in both the tumor microenvironment and the tumor macroenvironment. Some of these biomarkers have been validated as truly predictive of immunotherapy benefit using cohorts from randomized controlled trials, while others still require further validation of their predictive value. We also summarized the challenges and future directions of biomarker studies, hopefully facilitating the development of predictive biomarkers for immunotherapy that can eventually enter clinical practice.
Humans ; Tumor Microenvironment/immunology* ; Nasopharyngeal Carcinoma/immunology* ; Immunotherapy/methods* ; Nasopharyngeal Neoplasms/immunology* ; Biomarkers, Tumor/metabolism* ; Immune Checkpoint Inhibitors/therapeutic use*

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