Effects Of Tumor Microenvironment Research Articles

Acidic Lysosome-Anchoring Croconium-Based Nanoplatform for Enhanced Triple-Mode Bioimaging and Fe3+-Triggered Tumor Synergistic Therapy.

Metal-modulated croconium dyes with multimodal-imaging and synergistic therapy in the tumor microenvironment have exhibited great potential in tumor theranostics. However, their unideal structure optimization always weakened the efficacy of near-infrared fluorescence-photoacoustic (NIRF/PA) imaging and photothermal therapy (PTT). Here, we screened croconium dye containing two indole groups with better NIRF/PA imaging and PTT in their family, linked to two morpholine rings, and obtained CR-736, as a lysosome-targeting and Fe3+-modulated agent. The established CR-736-Fe3+ nanoplatform was accurately delivered to the breast tumor site, released CR-736 and Fe3+ in the lower acidic lysosome microenvironment, and activated pH-responsive NIRF/PA/magnetic resonance imaging and PTT. Furthermore, ferroptosis generated hydroxyl free radicals and lipid peroxide by consuming GSH and H2O2 by dint of the accumulation of Fe3+ in tumor cells, which resulted in the inhibition of the expression of heat shock proteins and the concomitant recovery of PTT. The synergistic therapy of PTT, ferroptosis, and chemodynamics was further optimized to the maximal extent in tumor lysosome acidic microenvironment and proved both in vitro and a mouse tumor model. This study opens a new avenue in designing excellent and unique croconium-based nanoplatforms, synergizing multiple tumor theranostic methods, and further optimizing the theranostic effects in tumor microenvironment.

Retracted: Effect of Tumor Microenvironment and Angiogenesis on Clinical Outcomes of Primary Central Nervous System Lymphoma.

[This retracts the article DOI: 10.1155/2021/3291762.].

Effects of Tumor Microenvironment on the Primo Vascular Pattern in the Mouse Model of Metastatic Breast Cancer.

: Tumor survival, promotion, and metastatic functions are regulated by the tumor microenvironment (TME). The primo vascular system (PVS), the third circulatory system in animals, is currently thought to be a highly effective pathway for the spread of cancer cells. : In the present study, we intend to determine the TME effects on the PVS pattern in breast cancer for the first time. : Heterotopic and orthotopic metastatic triple-negative breast cancer (TNBC) mice models were created. After 35 days, the skin was retracted, and a 2 cm skin incision was made up and down from the surface of the tumor tissue. In preparation for PVS staining, the dyes (trypan blue and alamarBlue) were injected throughout the tumor tissues. Under a stereomicroscope, PVS in heterotopic and orthotopic tumors was seen. : According to our data, there are no appreciable variations in PVS patterns and density between heterotopic and orthotopic animal models. Furthermore, alamarBlue is a good option for tumor PVS staining, as demonstrated by our research. : For the first time, our data gave significant new information about the PVS in TNBC. Creating new anti-cancer treatments may be made possible by a better understanding of the biological characteristics of the TME and PVS.

563 - The effect of tumor microenvironment and thymidylate synthase expression levels on growth and metastasis of colorectal cancer

563 - The effect of tumor microenvironment and thymidylate synthase expression levels on growth and metastasis of colorectal cancer

Comprehensive bioinformatics analysis of the role of VWF in the tumor microenvironment of malignant mesothelioma.

To explore the influence and effect of tumor microenvironment on the development of malignant mesothelioma using machine learning methods. 87 open cases were downloaded from the Cancer Genome Atlas database including transcriptome data, clinical data, and mutation data. The immune, stromal, and estimate scores were calculated for each case by using the ESTIMATE algorithm, and then the cases were grouped according to high and low stromal scores to predict all-cause survival in malignant mesothelioma cases. Their mutation data were analyzed to reveal the differences in mutated genes between the 2 groups, and then the von Willebrand factor (VWF) and FCRL3 genes were identified according to the intersection of DEGs and high-frequency mutated genes. Lastly, the correlation between VWF and the immune checkpoint of 22 kinds of immune cells was analyzed by using the CIBERSORT package of R software. A significant difference was found in the survival time of patients between the high and low stromal score groups. High expression of the VWF gene was negatively correlated with the prognosis of malignant mesothelioma, and the expression of VWF was positively correlated with naive B cells and activated CD4 memory T cells and negatively correlated with NK cells. The results revealed that high expression of VWF may involve in the development of malignant mesothelioma, and the anti-CTLA4 immune checkpoint treatment may have certain efficacy.

Effect of tumor microenvironment on chemotherapy response of patients with triple-negative breast cancer receiving neoadjuvant chemotherapy.

590 Background: Triple-negative breast cancer (TNBC) is a breast cancer subtype that has poor prognosis and exhibits a unique tumor microenvironment, including the corresponding immunological environment. Analysis of the tumor microbiome has indicated a relationship between the tumor microenvironment and treatment response. Therefore, we attempted to reveal the role of the tumor microbiome in patients with TNBC that were receiving neoadjuvant chemotherapy. Methods: We collected TNBC patient RNA-seq samples from the Gene Expression Omnibus (GEO; n of pathological complete response [pCR] = 38, n of residual disease [RD] = 50) and extracted microbiome count data using Kraken2 and Bracken. Differential and relative abundance were estimated with linear discriminant analysis effect size (LEfSe). We calculated the immune cell fraction with CIBERSORTx and conducted survival analysis using the Cancer Genome Atlas patient data (n = 115). Correlations between the microbiome and immune cell compositions were analyzed and a prediction model was constructed to estimate drug response using random forest (RF) and support vector machine (SVM). Results: Among the drug response group, the beta diversity varied considerably; consequently, 20 genera and 24 species were observed to express a significant differential and relative abundance using LEfSe analysis. The drug response prediction model accuracy exhibited 76.47 and 88.24 percent in RF and SVM, respectively; specifically, Pandoraea pulmonicola and Brucella melitensis were found to be important features in determining drug response. In correlation analysis, Geosporobacter ferrireducens, Streptococcus sanguinis, and resting natural killer cells were the most correlated factors in the pCR group, whereas Nitrosospira briensis, Plantactinospora sp. BC1, and regulatory T cells (Tregs) were key features in the RD group. Further, M2 macrophages and Brucella showed significant differences in survival between the pCR and RD groups (p < 0.05). Conclusions: Our study demonstrated that the microbiome analysis of tumor tissue can predict chemotherapy response of patients with TNBC receiving neoadjuvant chemotherapy. Further, the immunological tumor microenvironment may be impacted by the tumor microbiome, thereby affecting the corresponding survival and treatment response.

Effect of tumor microenvironment and role of Lymphocyte pattern on biological behavior and survival outcomes in oral squamous cell carcinoma

Effect of tumor microenvironment and role of Lymphocyte pattern on biological behavior and survival outcomes in oral squamous cell carcinoma

Effect of tumor microenvironment on ferroptosis: inhibition or promotion.

Ferroptosis is a type of lipid peroxidation-induced, iron-dependent programmed cell death. Emerging evidence suggests that ferroptosis is intimately connected to tumorigenesis, development, treatment and plays a major role in tumor immune regulation. This study focused on the connection between ferroptosis and immune regulation, which may offer a theoretical basis for targeting ferroptosis and tumor immunotherapy.

Prognostic prediction and multidimensional dissections of a macrophages M0-related gene signature in liver cancer.

Liver hepatocellular carcinoma (LIHC) is the seventh most commonly diagnosed malignancy and the third leading cause of all cancer death worldwide. The undifferentiated macrophages M0 can be induced into polarized M1 and M2 to exert opposite effects in tumor microenvironment. However, the prognostic value of macrophages M0 phenotype remains obscure in LIHC. The transcriptome data of LIHC was obtained from TCGA database and ICGC database. 365 LIHC samples from TCGA database and 231 LIHC samples from ICGC database were finally included. Macrophages M0-related genes (MRGs) were screened by Pearson correlation analysis and univariate Cox regression analysis based on the infiltration level of Macrophages M0. LASSO regression analysis was employed to construct a prognostic signature based on MRGs, and risk scores were accordingly calculated. Then we investigated the MRGs-based prognostic signature with respects to prognostic value, clinical significance, strengthened pathways, immune infiltration, gene mutation and drug sensitivity. Furthermore, the expression pattern of MRGs in the tumor microenvironment were also detected in LIHC. A ten-MRG signature was developed and clarified as independent prognostic predictors in LIHC. The risk score-based nomogram showed favorable capability in survival prediction. Several substance metabolism activities like fatty acid/amino acid metabolism were strengthened in low-risk group. Low risk group was deciphered to harbor TTN mutation-driven tumorigenesis, while TP53 mutation was dominant in high-risk group. We also ascertained that the infiltration levels of immune cells and expressions of immune checkpoints are significantly influenced by the risk score. Besides, we implied that patients in low-risk group may be more sensitive to several anti-cancer drugs. What's more important, single-cell analysis verified the expression of MRGs in the tumor microenvironment of LIHC. Multidimensional evaluations verified the clinical utility of the macrophages M0-related gene signature to predict prognosis, assist risk decision and guide treatment strategy for patients with LIHC.

Characterization of immature ovarian teratomas through single-cell transcriptome.

Immature ovarian teratomas are a type of malignant germ cell tumor composed of complicated cell types and are characterized by pathological features of immature neuroectodermal tubules/rosettes. However, there is a lack of understanding of patient-derived immature ovarian teratomas (PDT) at the single cell level. Moreover, whether stem cell lines derived from immature teratomas (CDT) can be used as models for research on PDT remains to be elucidated. Single-cell RNA sequencing (scRNA-seq) and subsequent bioinformatic analysis was performed on three patient-derived immature ovarian teratomas (PDT) samples to reveal the heterogeneity, evolution trajectory, and cell communication within the tumor microenvironment of PDT. Validations were conducted in additional seven samples through multiplex immunofluorescence. A total of qualified 22,153 cells were obtained and divided into 28 clusters, which can match to the scRNA-seq annotation of CDT as well as human fetal Cell Atlas, but with higher heterogeneity and more prolific cell-cell crosstalk. Radial glia cells (tagged by SOX2) and immature neuron (tagged by DCX) exhibited mutually exclusive expression and differentiated along distinct evolutionary trajectory from cycling neural progenitors. Proportions of these neuroectodermal cell subtypes may play important roles in PDT through contributing to the internal heterogeneity of PDTs. Moreover, the immune cells in PDTs were infiltrated rather than teratoma-derived, with more abundant macrophage in immature neuron than those in radial glia cells, and the infiltrated macrophage subtypes (i.e., M1 and M2) were significantly correlated to clinical grade. Overall, suppressed evolution process and transcriptome regulation in neuroectodermal cells, reduced cell-cell crosstalk, higher M1/M2 proportion ratio, and enhanced T cell effects in tumor microenvironment are enriched in patients with favorable prognosis. This study provides a comprehensive profile of PDT at the single cell level, shedding light on the heterogeneity and evolution of neuroectodermal cells within PDTs and the role of immune cells within the tumor microenvironment. Also, our findings highlight the potential usage of CDTs as a model for research on PDT.

Voluntarily wheel running inhibits the growth of CRPC xenograft by inhibiting HMGB1 in mice

IntroductionExercise has been proved to reduce the risk of recurrence and mortality of cancer. Emerging evidence indicated that exercise may regulate both systematical and local metabolism, immunity and other ways. Although the role of exercise in inhibiting castration-resistant prostate cancer is well established, the underlying mechanism remains unclear. MethodTwenty C57BL/6 male mice were used to construct CRPC xenograft models and randomly divided into exercise group (n = 10) and control group (n = 10). After exercised with voluntarily wheel running for 21 days, the mice were sacrificed and the tumor tissues and serum were collected. TUNEL staining was used to detect the apoptosis of tumor cells. The expression of PI3K signal pathway and apoptosis related proteins were detected by Western blot. The expression of AR and HMGB1 were examined by Western blot and Immunohistochemical staining. IFN-γ, TNF-α, TGF-β, IL-4, IL-6, IL-10 in serum was examined using ELISA kits. ResultsVoluntarily wheel running inhibited the growth of CRPC xenografts, inhibited the proliferation of tumor cells and promoted the apoptosis of tumor cells. HMGB1 levels in serum and tumor tissues were significantly reduced after exercise, which enhanced local immunity by inducing more leukocyte infiltration and inhibited systemic inflammatory response by regulating cytokines. ConclusionVoluntary wheel running can down-regulate the expression of HMGB1 in serum and transplanted tumor tissues, inhibit proliferation and promote apoptosis of tumor cells, enhance immune cell infiltration and systemic inflammatory response, and regulate local anti-tumor effects in tumor microenvironment.

Abstract 2551: Sexual dimorphic effects of tumour microenvironment dictate melanoma progression and therapy resistance

Abstract Melanoma is a disease of ageing with elderly patients showing poorer prognosis than younger patients. The role of the ageing microenvironment in melanoma progression is now recognized where aged stromal cells undergo cellular and molecular changes that are tumour permissive. However, sex-based differences in melanoma incidence and outcome have also been observed even when adjusted for several prognostic factors including age, with men having poorer outcomes compared to women. While the mechanisms underlying this disparity are not well understood but attributed to sex-specific behaviors as well as to the biologically intrinsic differences. In addition, most preclinical studies have ignored the contribution of the host sex and age to therapy response, with majority of the studies typically performed in 6-8 week old male mice. Dermal fibroblasts (dFs) are established to have profound impact on melanoma progression. We examined if both sex-dependent and age-related changes in dFs can alter the course of melanoma tumor growth, visceral metastasis, dormancy and variable responses to targeted therapy. We find that age-matched female dFs undergo early replicative senescence accompanied by reduced proliferation and morphology change. Despite being senescent, age-matched female dFs showed reduced SASP characteristics. This was assessed by testing dFs derived conditioned media on melanoma cells in spheroid invasion and resistance to BRAF/MEK inhibition which showed elevated expression of invasive drivers and oxidative stress from aged male dFs derived conditioned media. This was also apparent in vivo in syngeneic immunocompetent C57Bl/6 mice that showed reduced tumor growth and increased invasion specific to the aged male host. Our data provides an integrated view of how age and sex attributes of dFs within the microenvironment contribute to disease progression. Bridging this knowledge gap will improve patient stratification and assist in tailoring the therapy and achieve gender-equitable healthcare. Citation Format: Yash Chhabra, Mitchell Fane, Laura Huser, Daniel Zabransky, Megan Brezka, Gloria Marino, Alexis Carey, Ashani Weeraratna. Sexual dimorphic effects of tumour microenvironment dictate melanoma progression and therapy resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2551.

The effect of mesenchymal stromal cells ın the microenvironment on cancer development

Inflammatory signals secreted from the tumor microenvironment are thought to promote tumor growth and survival. It has been reported that stromal cells in the tumor microenvironment have similar characteristics to tumor-associated cells. In addition miRNAs play critical roles in various diseases, including cancer. In this study, we aimed to investigate the effects of co-culture of cancer cells and stromal cells isolated from normal and malignant breast tissue on each other and the possible effects of miRNAs on these interactions. The characterized stromal cells were co-cultured with an MDA-MB-231 cancer cell line. The proliferation capacity of the experimental groups was evaluated using the WST-1 assay. The expression of breast cancer-specific miRNAs and related genes were assessed by real-time PCR. ELISA assay was performed to determine the concentration of some cytokines and chemokines. We found that the microenvironment plays an important role in the development of cancer, confirming the changes in the expression of oncogenic and tumor suppressor miRNA and their target genes after co-culture with malignant stromal cells. As a result of the studies, specific gene expressions of related signaling pathways were detected in correlation with miRNA changes and the effects of tumor microenvironment on tumorigenesis were revealed in detail. miRNAs have been shown to play an important role in cancer development in recent studies. The idea that these small molecules can be used in diagnosis and treatment is becoming stronger day by day. We believe that new treatment approaches involving the tumor microenvironment and using miRNAs as markers are promising.

Relationship between IL-1β and IL-8 serum concentrations in patients with metastatic melanoma taking checkpoint inhibitors.

e21510 Background: Melanoma is a disease that is most often treated with immune checkpoint inhibitors (ICI). The principle mechanism of ICI is based on the activation of the antitumor immune response. This therapy is not effective in all patients, which may be due to the immunosuppressive effect of tumor microenvironment (TME). IL-1β is one of the most important participants in the TME, however, it is difficult to determine it in blood serum, in contrast to IL-8, the synthesis of which is induced by IL-1β. The study aims to determine the relationship between IL-1β and IL-8 in patients with metastatic (mts) melanoma and to reveal their diagnostic significance. Methods: The study involved 28 patients (pts) with mts melanoma taking ICI. The level of IL-1β and IL-8 in blood serum was determined using the ELISA method. Statistical analysis was performed in GraphPad Prism 6 (Graph Pad Software, USA) using Fisher, Mann-Whitney, ROC, Wilcoxon matched-pairs signed rank test, Spearman statistical analysis. Results: IL-1β was detected in 35.5% (11/31) of patients before therapy, while an elevated level was recorded in only one patient. IL-8 was found in all patients, an elevated level before therapy was observed in 64.5% (20/31) of cases, after 2-3 months - in 35.5% (11/31). During ICI therapy, a statistically significant decrease in the concentration of IL-1β (p = 0.0498) and IL-8 (p = 0.0002) were observed. In the presence of IL-1β, the level of IL-8 was statistically higher (139.6±65.26 pg/ml), p = 0.024, while a mean positive correlation was found between IL-1β and IL-8 concentrations (R = 0.6469, p = 0.035). According to ROC analysis (Area = 0.76), with an increase in the concentration of IL-8 more than 42.31 pg/ml with a diagnostic sensitivity of 66.67% and a specificity of 90.00%, it can be assumed that the level of IL-1β will be detected in the patient (p = 0.025). Conclusions: According to the study, with an IL-8 concentration of more than 42.31 pg/ml in patients with mts melanoma, the presence of IL-1β in the blood serum can be expected. At the same time, the level of IL-8 correlated with the level of IL-1β. It can be assumed that high level of IL-8 may indicate the overexpression IL-1β in TME and it`s high activity, which may be associated with the possible risk of low ICI efficacy.

A three-dimensional biomimetic microfluidic chip to study the behavior of hepatic stellate cell under the tumor microenvironment

In this paper, we designed a three-dimensional cell co-cultured microfluidic chip, which generated interstitial flow and oxygen gradient to simulate the complex tumor microenvironment. It consisted of five parallel cell culture channels and one hypoxic channel. These channels were constructed for the culture of mouse liver tumor cells (Hepa1-6), mouse liver stellate cells (JS-1), the simulation of extracellular matrix, complex biochemical factors (hypoxia and interstitial flow), and the supply of cellular nutrients. The 3D-interstitial flow-hypoxia model was used to study the behavior of JS-1 cells under the effect of tumor microenvironment (TME). The results showed that by co-cultured with Hepa1-6 cells, hypoxia of Hepa1-6 cells, and adding TGF-β1 by interstitial flow, the migration of JS-1 cells could be promoted. Similarly, activated JS-1 cells could led to the epithelial-mesenchymal transformation in co-cultured Hepa1-6 cells, which secreted more TGF-β1.

SDHB and SDHD silenced pheochromocytoma spheroids respond differently to tumour microenvironment and their aggressiveness is inhibited by impairing stroma metabolism

Germline mutations in more than 20 genes, including those encoding for the succinate dehydrogenase (SDH), predispose to rare tumours, such as pheochromocytoma/paraganglioma (PPGL). Despite encoding for the same enzymatic complex, SDHC and SDHD mutated PHEO/PGLs are generally benign, while up to 80% of SDHB mutated ones are malignant.In this study, we evaluated the different effects of tumour microenvironment on tumour cell migration/invasion, by co-culturing SDHB or SDHD silenced tumour spheroids with primary cancer-associated fibroblasts (CAFs). We observed that SDHD silenced spheroids had an intermediate migration pattern, compared to the highest migration capability of SDHB and the lowest one of the wild type (Wt) spheroids. Interestingly, we noticed that co-culturing Wt, SDHB and SDHD silenced spheroids with CAFs in low glucose (1 g/l) medium, caused a decreased migration of all the spheroids, but only for SDHB silenced ones this reduction was significant. Moreover, the collective migration, observed in high glucose (4.5 g/l) and characteristic of the SDHB silenced cells, was completely lost in low glucose. Importantly, migration could not be recovered even adding glucose (3.5 g/l) to low glucose conditioned medium.When we investigated cell metabolism, we found that low glucose concentration led to a reduction of oxygen consumption rate (OCR), basal and maximal oxidative metabolism, and ATP production only in CAFs, but not in tumour cells. These results suggest that CAFs metabolism impairment was responsible for the decreased invasion process of tumour cells, most likely preventing the release of the pro-migratory factors produced by CAFs.In conclusion, the interplay between CAFs and tumour cells is distinctive depending on the gene involved, and highlights the possibility to inhibit CAF-induced migration by impairing CAFs metabolism, indicating new potential therapeutic scenarios for medical therapy.

Hypoxia Drives Centrosome Amplification in Cancer Cells via HIF1α-dependent Induction of Polo-Like Kinase 4.

Hypoxia drives CA in cancer cells by regulating expression of PLK4, uncovering a novel HIF1α/PLK4 axis.

What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review. Part 7: PD-L1 Expression in Liquid Biopsy.

Liquid biopsy is an accessible, non-invasive diagnostic tool for advanced prostate cancer (PC) patients, potentially representing a real-time monitoring test for tumor evolution and response to treatment through the analysis of circulating tumor cells (CTCs) and exosomes. We performed a systematic literature review (PRISMA guidelines) to describe the current knowledge about PD-L1 expression in liquid biopsies of PC patients: 101/159 (64%) cases revealed a variable number of PD-L1+ CTCs. Outcome correlations should be investigated in larger series. Nuclear PD-L1 expression by CTCs was occasionally associated with worse prognosis. Treatment (abiraterone, enzalutamide, radiotherapy, checkpoint-inhibitors) influenced PD-L1+ CTC levels. Discordance in PD-L1 status was detected between primary vs. metastatic PC tissue biopsies and CTCs vs. corresponding tumor tissues. PD-L1 is also released by PC cells through soluble exosomes, which could inhibit the T cell function, causing immune evasion. PD-L1+ PC-CTC monitoring and genomic profiling may better characterize the ongoing aggressive PC forms compared to PD-L1 evaluation on primary tumor biopsies/prostatectomy specimens (sometimes sampled a long time before recurrence/progression). Myeloid-derived suppressor cells and dendritic cells (DCs), which may have immune-suppressive effects in tumor microenvironment, have been found in PC patients circulation, sometimes expressing PD-L1. Occasionally, their levels correlated to clinical outcome. Enzalutamide-progressing castration-resistant PC patients revealed increased PD-1+ T cells and circulating PD-L1/2+ DCs.

PD‐1+CXCR5‐CD4+ T cells are correlated with the severity of lung adenocarcinoma malignant processes

AbstractPeripheral helper T cells (Tph), characterized by PD‐1+CXCR5‐CD4+ phenotypes cells, played critical roles in inflamed tissues. Yet, to date, no researches were developed for lung adenocarcinoma (LADC) that was associated with worse outcome, advanced invasion and chronic inflammation in lung cancer cases. Accordingly, we aimed to investigate the impact of Tph cell subsets on the disease progress in peripheral blood and tumour tissue of patients with LADC. The percentages of Tph cell subsets in peripheral blood and tumour tissues obtained from 35 LADC and 10 healthy controls were examined by flow cytometry. In addition, invasion and tumour node metastasis (TNM) stage were also determined by Spearman's correlation test to assess their association with Tph cell subset. Furthermore, the effects of tumour microenvironment on Tph were investigated. The present results revealed that the percentage of Tph cells significantly increased in PBMC compared with healthy controls. In addition, similar results were observed in tumour tissues of LADC patients when compared to tumour‐adjacent control tissue. In addition, Tph cells were highly activated, appearing as ICOS increased, and associated with LADC invasion, compared with healthy controls. Notably, tumour environment could prefer Tph cells to promote tumour malignancy. Tph cells were observed in PBMC and tumour tissues from patients with LADC and highly associated with LADC invasion. Altogether, the present study indicates that elevated Tph cells could primarily be used as a potential therapeutic target in LADC patients.

Understanding of catalytic ROS generation from defect-rich graphene quantum-dots for therapeutic effects in tumor microenvironment

Owing to their low cost, high catalytic efficiency and biocompatibility, carbon-based metal-free catalysts (C-MFCs) have attracted intense interest for various applications, ranging from energy through environmental to biomedical technologies. While considerable effort and progress have been made in mechanistic understanding of C-MFCs for non-biomedical applications, their catalytic mechanism for therapeutic effects has rarely been investigated. In this study, defect-rich graphene quantum dots (GQDs) were developed as C-MFCs for efficient ROS generation, specifically in the H2O2-rich tumor microenvironment to cause multi-level damages of subcellular components (even in nuclei). While a desirable anti-cancer performance was achieved, the catalytic performance was found to strongly depend on the defect density. It is for the first time that the defect-induced catalytic generation of ROS by C-MFCs in the tumor microenvironment was demonstrated and the associated catalytic mechanism was elucidated. This work opens a new avenue for the development of safe and efficient catalytic nanomedicine.