The premetastatic niche (PMN) represents a metastasis-facilitative microenvironment established prior to tumor dissemination, initiated by vascular leakage and endothelial cell (EC) functional remodeling. ECs play pivotal roles as bridges in different stages of the metastatic cascade. As critical stromal components within the PMN, ECs not only drive angiogenesis but also actively orchestrate immune suppression, extracellular matrix (ECM) remodeling, and the inflammatory signaling characteristic of PMN formation, with multiple specific signaling pathways such as VEGF/Notch playing a crucial role. With the evolving understanding of the role of ECs in controlling tumor metastasis, therapeutic strategies targeting ECs within the PMN, such as antiangiogenic therapy (AAT), targeting of endothelial glycocalyx (GCX), inhibition of tumor-derived exosome (TDE) and angiocrine signaling, are becoming research hotspots. This review systematically delineates the cellular and molecular composition of PMNs, dynamically dissects their spatiotemporal evolution, and highlights organ-specific mechanisms of EC-driven PMN establishment. Furthermore, we summarize emerging EC-targeted therapeutic strategies, providing innovative insights for inhibiting tumor metastasis.

This study aims to evaluate the efficacy and safety of anlotinib combined with immune checkpoint inhibitors (ICIs) in patients with previously immunotherapy-treated extensive-stage small cell lung cancer (ES-SCLC).

Cholangiocarcinoma (CCA) is an aggressive, heterogeneous malignancy with limited effective treatment options. One of the key epigenetic dysregulations in CCA is aberrant DNA hypermethylation, suggesting that targeted DNA methylation is a promising therapeutic strategy for this disease. However, there is still limited information on how effective DNA demethylating agents are in the treatment of CCA in the clinical setting, and further studies are urgently needed to evaluate their potential benefits. Here, we established four patient-derived CCA cell lines and demonstrated that the DNA methyltransferase (DMNT) inhibitors decitabine and azacitidine had minimal effects on inhibiting CCA proliferation. A combinatorial drug screen identified PARP inhibitors as sensitizers that synergistically enhanced the antitumor effects of decitabine. The combination of DNMT inhibitors and PARP inhibitors therapeutically inhibited the growth of CCA cancers in multiple in vitro cancer cell lines and organoid models, as well as in vivo cell line-derived xenografts, patient-derived xenograft models, and CCA in mice induced by hydrodynamic tail vein injection. Mechanistically, transcriptomic profiling analysis showed that combination treatment activated the inflammatory signaling pathway and suppressed the cell cycle-related pathways in CCA. In addition, the combination synergistically induced DNA damage and cellular senescence of CCA cancer cells. Together, our study provides a preclinical proof-of-concept for the use of DNMT inhibitors in combination with PARP inhibitors as a novel therapeutic strategy and potentially optimizes current clinical practice in the treatment of CCA.

H. pylori infection is closely associated with the tumor microenvironment (TME) in gastric cancer (GC), yet its underlying mechanism is elusive. Hence, it is imperative to explore the microenvironment and drug resistance arising from H. pylori to enhance therapeutic strategies for GC.

This investigation seeks to examine the association between spleen volume and prognosis in cancer patients undergoing immune checkpoint inhibitor (ICI) treatment.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment for different types of cancers, providing significant clinical benefits. However, these therapies are associated with various immune-related adverse events (irAEs), including hepatic manifestations such as hepatitis, sinusoidal obstruction syndrome (SOS), and nodular regenerative hyperplasia. Among these, regenerative hepatic pseudotumors (RHPs) are exceptionally rare and poorly described in literature. Here, we report the case of a 66-year-old man with metastatic non-small-cell lung cancer (NSCLC) who developed a hepatic pseudotumor during routine imaging following treatment with the anti-programmed cell death 1 (PD-1) therapy, tislelizumab. Despite the presence of a hepatic lesion on imaging, the patient exhibited no clinical symptoms or biochemical evidence of severe immune-mediated hepatitis. Following cessation of anti-PD-1 therapy and initiation of systemic steroid therapy, the hepatic pseudotumors stabilized without further growth. The findings suggest that ICI therapy may be associated with the development of regenerative hepatic pseudotumor (RHP). Given the nonspecific and potentially misleading imaging features of RHP, biopsy is essential for accurate diagnosis and differentiation from malignant lesions such as hepatic metastases. Early histological evaluation through biopsy can prevent unnecessary interventions and guide appropriate management in patients presenting with liver lesions during or after ICI therapy. This case suggests a possible association between the development of RHP and tislelizumab treatment. The effect of ICI-induced hepatic pseudotumors on NSCLC progression is unclear and requires further investigation.

Immune checkpoint inhibitors (ICIs) have transformed cancer therapy but are limited by immune-related adverse events (irAEs). This study aimed to assess peripheral T cell profiles to identify irAEs biomarkers and construct predictive models.

Immune checkpoint inhibitors (ICIs) significantly prolong the survival of cancer patients. including gastric adenocarcinoma (GAC) and esophageal squamous cell carcinoma (ESCC) patients. Immune-related adverse events (irAEs) are inevitably involved in ICIs treatment sometimes with severe consequences. Extreme caution is necessary for predicting irAEs and precisely screening of appropriate patients. We evaluated the association of interleukin-6 (IL-6) with irAEs and their impacts on ICIs treatment effectiveness in advanced GAC and ESCC patients.

Immune checkpoint inhibitors (ICI) have revolutionized the treatment of solid tumors. However, they can induce immune-related adverse effects (irAEs) that can affect any organ. These irAEs are different from the side effects of traditional oncological treatments and require specific management. Given the increasing use of ICI, first-line care will increasingly need to manage these irAEs. This article aims to assist in the implementation of the guidelines for managing irAEs, with a particular focus on aspects related to first-line care.

Benign lymphangioendothelioma is a rare tumor originating from lymphatic vessels. Its underlying mechanisms remain unclear, and effective therapeutic interventions are limited.

PurposeThis study aims to develop a scoring system tailored for Asian populations through quantifying VTE risk in a cohort of hospitalized cancer patients receiving immune checkpoint inhibitors.MethodsWe retrospectively analyzed 1171 patients treated with PD-1/PD-L1 inhibitors at Zhongshan Hospital (Xiamen), Fudan University between January 2021 and December 2023. We gathered information on every patient from the electronic database of the hospital and follow-up.The collected data were statistically analyzed to obtain risk factors for for VTE and validation of the score. Finally, we validated the precision of the model in prediction.ResultsBased on these findings, we developed the L2HSDK score,that identified seven independent risk factors for VTE:liver cancer, smoking, diabetes mellitus, liver dysfunction, cardiovascular history, and a Khorana Risk Score ≥ 3. The patients were divided into low, moderate, and high VTE risk groups. Significant differences in VTE incidence were observed across these groups, with the high-risk group showing a markedly higher risk. The validation of the model demonstrates the precision of the L2HSDK score in prediction.ConclusionThe L2HSDK score offers a more precise and tailored method for assessing VTE risk in cancer patients receiving PD-1/PD-L1 inhibitors therapy in mainland China, surpassing the widely used Khorana Risk Score by accounting for regional and treatment-specific factors.

Several mechanisms are involved in the resistance to endocrine therapy (ET) in estrogen receptor (ERα)-positive breast cancer (BC), including acquired mutations of ERα gene (ESR1). For example, the frequent mutation, Y537S, was shown to trigger a constitutively active receptor leading to reduced affinity for both agonist and antagonist ligands. The development of more comprehensive therapies remains a challenge in BC patients exhibiting activating mutations in ERα. Here, we show that Poly (ADP-ribose) polymerase-1 (PARP-1) may be considered as a novel therapeutic target in ERα-positive BC.

Non-small cell lung cancer (NSCLC) accounts for 85-90% of global lung cancer cases and causes over 1.7 million deaths annually worldwide. Despite therapeutic advancements, existing treatments remain expensive and are often associated with significant side effects, underscoring the need for alternative drug candidates. Natural compounds offer promising prospects as safer and more affordable therapeutic options for NSCLC. Toxicodendron succedaneum, a medicinally important plant species from the family Anacardiaceae, contains a diverse phytoconstituents with potential anticancer activity. Investigating these bioactive compounds may uncover therapeutic potential to facilitate NSCLC drug discovery. In this study, a comprehensive structure-based drug design approach was employed to identify drug candidates targeting the extracellular signal-regulated kinase 2 (ERK2) receptor. Using molecular docking, molecular dynamics (MD) simulation, ADMET analysis, MM/GBSA calculations, and DFT assessments, two lead compounds: rhusflavone ( - 10.9 kcal/mol) and hinokiflavone ( - 9.9 kcal/mol), were identified, both revealing favorable drug-likeness and toxicity profiles. MD simulation spanning 500 ns timescale confirmed the structural stability of the identified leads, further corroborated by principal component analysis (PCA) and Gibbs free energy landscape (FEL) evaluations. Rhusflavone emerged as the most promising candidate, with a free binding energy of - 57.15 ± 5.28 kcal/mol. DFT analysis revealed enhanced molecular reactivity of the lead compounds upon transitioning from the free to the bound states. These results could contribute to the development of novel lung anticancer drugs, warranting further in vitro and in vivo validation.

Chemotherapy is one of the most frequent therapeutic options in cancer patients. Cisplatin (CDDP) is widely used as one of the first-line platinum-based drugs in metastatic tumors. However, CDDP resistance is always one of the main therapeutic challenges in cancer patients. Considering the side effects of CDDP in cancer patients, the prediction of CDDP response can improve the management of tumor therapy. Therefore, it is necessary to investigate the molecular mechanisms involved in CDDP resistance in order to predict CDDP response in cancer patients. CDDP resistance is contributed with different cellular processes such as DNA repair, drug efflux, and signaling pathways. WNT/β-catenin pathway has a key role in tumor growth and drug resistance. β-catenin is considered as a key component of the WNT pathway, which can regulate the CDDP response in tumor cells by regulation of WNT target genes. In addition to the WNT pathway, β-catenin can also be regulated by the other signaling pathways. Deregulation of β-catenin is associated with CDDP resistance. Therefore, in the present review, we discussed the role of β-catenin in regulation CDDP response in tumor cells. It has been reported that β-catenin mainly promotes CDDP resistance in various cancers, whose function can be affected by other signaling pathways and transcription factors. This review can be an effective step toward introducing β-catenin as a prognostic marker as well as a therapeutic target in CDDP-resistant cancer patients.

Cysteine reactivity profiling is recognized as a powerful and versatile chemoproteomic technology to study the cysteinome in native biological systems. It involves the use of chemical probes that covalently bind to reactive cysteines, enabling the enrichment and quantitively analysis of cysteine abundance through mass spectrometry. Cysteines play critical roles in maintaining cellular redox homeostasis by dynamically switching between their reduced and oxidized forms during redox perturbations. Here, we described a detailed workflow of sample preparation for cysteine-based chemical proteomics, to systematically identify cysteines that are modified by anticancer drug induced ROS.

While immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, they can trigger severe immune-related adverse events (irAEs). The safety and efficacy of ICI retreatment after severe irAEs remain poorly understood.

The prognosis is still dismal, although several tyrosine kinase inhibitors (TKIs) with/without immune checkpoint inhibitors (ICIs) have shown promising results in the treatment of biliary tract carcinoma (BTC). However, the combination of hepatic artery infusion chemotherapy (HAIC) with ICIs and TKIs may have potential in patients with BTC, according to the success of such a regimen for hepatocellular carcinoma. Hence, this study aimed to evaluate the preliminary efficacy and safety profile of combination therapy with HAIC plus ICI and lenvatinib in BTC patients.

The standard treatment for various types of cancers typically involves the combination of concurrent localized radiotherapy and systemic chemotherapy. However, no treatment options have been reported that utilize chemotherapy cascade-enhanced radiotherapy. In this study, we report a core-satellite nanomedicine designed to enhance radiotherapeutic effects through a cascade mechanism by triggering the release of a potent chemotherapeutic agent in response to trypsin. We synthesized a functional enzyme-sequential responsive nanomedicine, DOX@Gel-DEVD-AuNR, which consists of gelatin nanoparticles loaded with the chemotherapeutic drug doxorubicin (DOX). These nanoparticles are covalently linked to gold nanorods (AuNR) via a caspase-3 specific DEVD peptide substrate. Upon trypsin activation, the DOX@Gel-DEVD-AuNR formulation releases DOX, thereby enhancing chemotherapy efficacy against tumors. Simultaneously, it activates caspase-3, inducing the aggregation of AuNRs, which in turn activates a near-infrared-II photoacoustic signal. This signal is crucial for determining the optimal timing for X-ray irradiation. The resulting large-size AuNRs aggregates promote their accumulation within tumors by preventing the migration and backflow of AuNRs, thereby improving radiotherapeutic effects. Consequently, when combined with image-guided X-ray irradiation, DOX@Gel-DEVD-AuNR induces significant cytotoxicity in cancer cells and effectively inhibits tumor growth. Our study underscores the potential application of enzyme catalysis-mediated chemistry in activating nanomedicine for activatable image-guided chemotherapy cascade-enhanced radiotherapy.

The development of effective drug delivery strategy by employing novel nano-careers are advantageous for targeted and controlled drug release. The present work describes about such a strategy in the form of a protein stabilized ultrasmall gold nanocluster as nano-career for the delivery of anticancer drug Gemcitabine (Gem). Gold nanocluster (AuNCs) stabilized by bovine serum albumin (BSA) was synthesized and characterized in detail including its stability, size distribution, toxicity, and photo-physical properties. It was revealed that monodispersed gold particles (~ 1.5 nm) dispersible in aqueous phase with unique optical absorption and emission characteristics (λabs = 450 nm, λemi = 650 nm), high stability and minimum toxicity was obtained. Afterward, an anticancer drug (Gem) was conjugated with the gold cluster through simple chemical mixing resulting in the formation of 55% drug load Au nanocluster (Gem-AuNCs-BSA). The resultant Gem-AuNCs-BSA showed enhanced delivery of drug and therapeutic effects for the treatment of breast cancer and lung cancer with better efficacy than free Gemcitabine.

The efficacy of 5-fluorouracil treatment for colorectal cancer (CRC) is substantially compromised by drug resistance, although the underlying mechanisms remain unclear. In this research, we aimed to explore the role and mechanism of action of CXC motif chemokine ligand 5 (CXCL5) in 5-fluorouracil resistance. RNA sequencing was conducted to detect abnormally expressed genes in the 5-fluorouracil-resistant colon cancer cell line, HCT8-5FU. CXCL5 expression in CRC tissues and cell lines was evaluated using RT-qPCR, western blotting, and immunohistochemistry. In vivo and in vitro assays were conducted to evaluate the role of CXCL5 in the promotion of CRC progression. Mass spectrometry and co-immunoprecipitation were employed to investigate the role of CXCL5 in CRC development and 5-fluorouracil resistance. Immunofluorescence and western blot analyses were employed to determine the subcellular localization of CXCL5 and its associated signaling pathways. CXCL5 expression was elevated in both CRC tissues and cell lines. CXCL5 promoted CRC cell growth and resistance to 5-fluorouracil in both in vitro and in vivo settings. Mechanistically, CXCL5 may modulate the MDM2/p53 axis to inhibit p21 by binding to RALY. In this study, CXCL5 accelerated CRC progression and increased CRC cell resistance to 5-fluorouracil via the inhibition of p21 expression. Thus, CXCL5 is a potential target for CRC therapeutic strategies.