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.

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.

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.

Small molecule activators of the mitochondrial caseinolytic protease P (ClpP agonists) can disrupt tumor metabolism and deprive tumors of their energy needs. The imipridone, ONC201, is a ClpP agonist currently undergoing clinical evaluation across multiple cancer types, while additional analogs with improved potency and selectivity are in preclinical development. Preclinical studies in mice have demonstrated a unique pharmacokinetic-pharmacodynamic (PK-PD) relationship for ONC201 characterized by prolonged pharmacology following a single dose. This motivated the selection of an initial human dosing regimen of every three weeks, and subsequent dose exploration studies in mice led to dose intensification in human patients. However, a systematic analysis of ClpP agonist PK-PD relationships has not been performed, and the optimal exposure profile for ClpP agonists remains undefined. To address this gap, we combined PK-PD modeling with a microfluidic perfusion platform as an animal-alternative approach for translational PK-PD of ClpP agonists. We demonstrate that the anti-proliferative effect on triple negative breast cancer cells correlates with the magnitude and duration of ClpP agonist exposure above a threshold concentration required for ClpP activation. Moreover, we demonstrate that PK-PD model simulations using parameters derived from microfluidic perfusion datasets can successfully predict the anti-tumor efficacy of a ClpP agonist in a mouse tumor xenograft study. These studies support the translational relevance of the animal-alternative in vitro PK-PD platform and its utility to help guide dose optimization of ClpP agonists as cancer therapeutics.

Objective responses to immune checkpoint inhibitors (ICI) in leiomyosarcoma (LMS) are rare. Response rates may be increased by combination with other drugs known to promote immune infiltration, such as poly(ADP-ribose) polymerase (PARP) inhibitors, which have led to benefit in BRCA-altered uterine LMS. We therefore evaluated the combination of a PARP inhibitor, rucaparib, and the anti-programmed death receptor-1 monoclonal antibody, nivolumab, in patients with advanced LMS and investigated its effects on the tumor immune microenvironment.

In this study, we designed and synthesized a novel polysaccharide-based fluorescent nanocarrier system, HPMC-AuNPs@1, for the delivery of plant extract compound 1. The HPMC-AuNPs@1 system was synthesized by functionalizing gold nanoparticles (AuNPs) with hydroxypropyl methylcellulose (HPMC) and loading Compound 1 into the system. The resulting nanocarrier exhibited a typical aggregation-induced emission (AIE) effect in aqueous media, showing strong green fluorescence in a DMSO-H2O (5:95) solution. Host-guest sensing experiments revealed that HPMC-AuNPs@1 demonstrated high selectivity for detecting carcinoembryonic antigen (CEA) among 14 different metallic ions and antigen molecules. A noticeable fluorescence shift occurred upon binding with CEA, and the detection limit for CEA was as low as 2.56 × 10-6 M. Additionally, we explored the potential therapeutic applications of HPMC-AuNPs@1 in cancer treatment, particularly in inducing pyroptosis, a form of programmed cell death. In vitro experiments with SNU-16 cells showed that HPMC-AuNPs@1 nanoparticles inhibited cancer cell proliferation by inducing pyroptosis. These findings suggest that HPMC-AuNPs@1 holds great promise as a therapeutic platform for cancer treatment, particularly in targeting cell proliferation pathways via pyroptosis induction.

Cell-free DNA (cfDNA) found in biofluids is increasingly being used in the diagnosis and treatment of a variety of disease states, including cancer. Though DNA is known to be susceptible to damage by many different chemotherapeutic compounds and genotoxic agents, the fact that cfDNA may be damaged and contain DNA adducts associated with specific exposures has not previously been considered to any significant extent. Here, using differential centrifugation of culture medium from cells treated with the anti-cancer drug cisplatin, we show that DNA containing cisplatin adducts is readily detectable in the extracellular milieu and is enriched in fractions known to contain small extracellular vesicles and cfDNA. However, our data indicates that this damaged cfDNA is non-vesicular in nature and likely represents fragments of chromatin. Dose and time course experiments suggest that the release of cfDNA containing cisplatin-DNA adducts is correlated with the activation of apoptotic signaling. Indeed, the generation of cisplatin-damaged cfDNA is exacerbated by the loss of nucleotide excision repair and is abrogated by caspase inhibition. Finally, we show that native cisplatin-damaged cfDNA, but not purified, protein-free cfDNA, can be taken up by cells by phagocytosis to result in the presence of cisplatin-DNA adduct-containing DNA in non-cisplatin-treated cells. These results indicate that tumors from patients undergoing cisplatin-based chemotherapy may shed damaged cfDNA that could have additional biological effects in bystander cells, which could both impact chemotherapeutic responses and lead to improved treatments and diagnostic tools for monitoring therapeutic efficacy.

Two marine actinomycete-like strains, MCC20T and MCC57, were isolated from Chanthaburi (Thailand) mangrove sediment. Their taxonomic classifications were established through a polyphasic approach. Despite differences in colony morphotypes, genetic and chemotaxonomic analyses confirmed them as the same species within the genus Streptomyces. Both strains contained ll-diaminopimelic acid in their cell wall, with glucose, mannose, ribose and rhamnose identified as whole-cell sugars. Their phospholipid profile comprises phosphatidylethanolamine, diphosphatidylglycerol, phosphatidylglycerol, phosphatidylinositol and phosphatidylinositol mannoside. The predominant fatty acids were iso-C15:0, anteiso-C15:0, iso-C16:0 and anteiso-C17:0 with MK-9(H8) as the primary menaquinone, while MK-9(H6) and MK-9(H4) were unique to strain MCC57. Both strains exhibited anticancer activity against colorectal (HCT116) and lung (A549) cancer cells, with strain MCC20T being more potent. Their 16S rRNA gene sequences showed 100% similarity, with 99.2% similarity to Streptomyces fumigatiscleroticus NBRC 12999T. Nevertheless, a phylogenomic tree placed them closer to Streptomyces spinosirectus CRSS-Y-16T, Streptomyces plumbidurans KC 17012T and Streptomyces spinosisporus 7R016T. Nearly 100% average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) values highlighted the identity of strains MCC20T and MCC57, while ANI (89.4%) and dDDH (35.5%) values were well below the respective 95 and 70% thresholds for related species. This supported their novelty. Based on their genotypes and phenotypes, strains MCC20T (=NBRC 117131T=TBRC 19240T) and MCC57 (=NBRC 117132=TBRC 19241) are identified as phenotypic variants of a new species, Streptomyces sediminimaris sp. nov., with strain MCC20T designated as the type strain (~9.2 Mb genome, 72.0 mol% G+C content).

Genomic instability is a hallmark of cancer and is associated with tumor progression and therapeutic resistance. Centrioles and centrosomes are a critical determinant of genomic stability. Polo-like kinase 4 (PLK4) is a serine-threonine kinase that plays a critical role in the regulation of centrosome duplication. PLK4 overexpression drives tumorigenesis and has been shown to be overexpressed in a wide variety of human tumors, where it is associated with more advanced disease and worse clinical outcomes. As such, there has been significant interest in pharmacologically targeting PLK4 using small-molecule inhibitors for therapeutic gain in multiple cancer types. In this review, we will discuss the functions of PLK4 in normal and oncogenic processes. We will further discuss the current state of PLK4 as a therapeutic target in cancer by reviewing the current literature on PLK4 inhibitors in both the preclinical and clinical space. Finally, we will discuss the emerging data exploring rational combinations of PLK4 inhibitors with DNA-damaging agents and immunotherapies as a means to unlock the potential of these agents in cancer therapy.

Paclitaxel is a potent agent against ovarian cancer. Hydrogen sulfide (H2S) is of particular interest in cancer treatment research. It is known that H2S has apoptotic and antiproliferative effects.

Inflammation is a hallmark of cancer, significantly contributing to tumor progression and therapeutic outcomes. Among the diverse cellular components of the tumor microenvironment, fibroblasts have been recognized as key regulators of inflammatory processes. Under tumor‑specific conditions, cancer‑associated fibroblasts (CAFs) undergo differentiation and promote tumor proliferation, metastasis and immune evasion via highly intricate mechanisms. This review provides a comprehensive analysis of the reciprocal interactions between CAFs and inflammation, elucidating the mechanisms by which CAFs induce pro‑inflammatory signaling and how inflammatory mediators, in turn, potentiate CAF activation and function. Furthermore, innovative therapeutic strategies, including the inhibition of stromal proteins, hypoxia‑inducible factor 1α and metabolic pathways associated with CAFs, as well as the application of nanoparticle‑based drug delivery systems, are examined for their potential to impede CAF‑mediated tumor progression. Pharmacological agents targeting CAF‑associated signaling pathways or inflammatory cytokines show dual efficacy by concurrently modulating inflammatory responses and CAF activity. These approaches frequently demonstrate improved therapeutic efficacy compared to interventions solely directed at CAF surface proteins, highlighting the therapeutic potential of concurrently addressing both inflammation and CAFs to enhance cancer treatment efficacy.