Two-dimensional nanomaterial-based photothermal therapy (PTT) is currently under intensive investigation as a promising approach toward curative cancer treatment. However, high toxicity, moderate efficacy, and low uniformity in shape remain critical unresolved issues that hamper their clinical application. Thus, there is an urgent need for developing versatile nanomaterials to meet clinical expectations. To achieve this goal, we developed a stable, highly uniform in size, and nontoxic nanomaterials made of tellurium-selenium (TeSe)–based lateral heterojunction. Systemic delivery of TeSe nanoparticles in mice showed highly specific accumulation in tumors relative to other healthy tissues. Upon exposure to light, TeSe nanoparticles nearly completely eradicated lung cancer and hepatocellular carcinoma in preclinical models. Consistent with tumor suppression, PTT altered the tumor microenvironment and induced immense cancer cell apoptosis. Together, our findings demonstrate an exciting and promising PTT-based approach for cancer eradication.
ObjectivePancreatic ductal adenocarcinoma (PDAC) is the most lethal malignancy and lacks effective treatment. We aimed to understand molecular mechanisms of the intertwined interactions between tumour stromal components in metastasis and to provide a new paradigm for PDAC therapy.DesignTwo unselected cohorts of 154 and 20 patients with PDAC were subjected to correlation between interleukin (IL)-33 and CXCL3 levels and survivals. Unbiased expression profiling, and genetic and pharmacological gain-of-function and loss-of-function approaches were employed to identify molecular signalling in tumour-associated macrophages (TAMs) and myofibroblastic cancer-associated fibroblasts (myoCAFs). The role of the IL-33–ST2–CXCL3–CXCR2 axis in PDAC metastasis was evaluated in three clinically relevant mouse PDAC models.ResultsIL-33 was specifically elevated in human PDACs and positively correlated with tumour inflammation in human patients with PDAC. CXCL3 was highly upregulated in IL-33-stimulated macrophages that were the primary source of CXCL3. CXCL3 was correlated with poor survival in human patients with PDAC. Mechanistically, activation of the IL-33–ST2–MYC pathway attributed to high CXCL3 production. The highest level of CXCL3 was found in PDAC relative to other cancer types and its receptor CXCR2 was almost exclusively expressed in CAFs. Activation of CXCR2 by CXCL3 induced a CAF-to-myoCAF transition and α-smooth muscle actin (α-SMA) was uniquely upregulated by the CXCL3–CXCR2 signalling. Type III collagen was identified as the CXCL3–CXCR2-targeted adhesive molecule responsible for myoCAF-driven PDAC metastasis.ConclusionsOur work provides novel mechanistic insights into understanding PDAC metastasis by the TAM-CAF interaction and targeting each of these signalling components would provide an attractive and new paradigm for treating pancreatic cancer.
Glucose uptake is essential for cancer glycolysis and is involved in non-shivering thermogenesis of adipose tissues1–6. Most cancers use glycolysis to harness energy for their infinite growth, invasion and metastasis2,7,8. Activation of thermogenic metabolism in brown adipose tissue (BAT) by cold and drugs instigates blood glucose uptake in adipocytes4,5,9. However, the functional effects of the global metabolic changes associated with BAT activation on tumour growth are unclear. Here we show that exposure of tumour-bearing mice to cold conditions markedly inhibits the growth of various types of solid tumours, including clinically untreatable cancers such as pancreatic cancers. Mechanistically, cold-induced BAT activation substantially decreases blood glucose and impedes the glycolysis-based metabolism in cancer cells. The removal of BAT and feeding on a high-glucose diet under cold exposure restore tumour growth, and genetic deletion of Ucp1—the key mediator for BAT-thermogenesis—ablates the cold-triggered anticancer effect. In a pilot human study, mild cold exposure activates a substantial amount of BAT in both healthy humans and a patient with cancer with mitigated glucose uptake in the tumour tissue. These findings provide a previously undescribed concept and paradigm for cancer therapy that uses a simple and effective approach. We anticipate that cold exposure and activation of BAT through any other approach, such as drugs and devices either alone or in combination with other anticancer therapeutics, will provide a general approach for the effective treatment of various cancers.
Background: The high lethal rate of pancreatic cancer is partly due to a lack of efficient biomarkers for screening and early diagnosis. We attempted to develop effective and noninvasive methods using 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) markers from circulating cell-free DNA (cfDNA) for the detection of pancreatic ductal adenocarcinoma (PDAC). Results: A 24-feature 5mC model that can accurately discriminate PDAC from healthy controls (area under the curve (AUC) = 0.977, sensitivity = 0.824, specificity = 1) and a 5hmC prediction model with 27 features demonstrated excellent detection power in two distinct validation sets (AUC = 0.992 and 0.960, sensitivity = 0.786 and 0.857, specificity = 1 and 0.993). The 51-feature model combining 5mC and 5hmC markers outperformed both of the individual models, with an AUC of 0.997 (sensitivity = 0.938, specificity = 0.955) and particularly an improvement in the prediction sensitivity of PDAC. In addition, the weighted diagnosis score (wd-score) calculated with the 5hmC model can distinguish stage I patients from stage II-IV patients. Conclusions: Both 5mC and 5hmC biomarkers in cfDNA are effective in PDAC detection, and the 5mC-5hmC integrated model significantly improve the detection sensitivity.
Conventional chemotherapy and photothermal therapy (PTT) face many major challenges, including systemic toxicity, low bioavailability, ineffective tissue penetration, chemotherapy/hyperthermia‐induced inflammation, and tumor angiogenesis. A versatile nanomedicine offers an exciting opportunity to circumvent the abovementioned limitations for their successful translation into clinical practice. Here, a promising biophotonic nanoplatform is developed based on the zirconium carbide (ZrC) nanosheet as a deep PTT‐photosensitizer and on‐demand designed anticancer prodrug SN38‐Nif, which is released and activated by photothermia and tumor‐overexpressed esterase. In vitro and in vivo experimental evidence shows the potent anticancer effects of the integrated ZrC@prodrug biophotonic nanoplatform by specifically targeting malignant cells, chemotherapy/hyperthermia‐induced tumor inflammation, and angiogenesis. In mouse models, the ZrC@prodrug system markedly inhibits tumor recurrence, metastasis, inflammation and angiogenesis. The findings unravel a promising biophotonic strategy for precision treatment of cancer.
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