Search Results (763)

Background: Immune checkpoint inhibitors (ICIs) have limited efficacy in proficient mismatch repair (pMMR) and microsatellite stability (MSS) metastatic colorectal cancer (mCRC). Inhibition of vascular endothelial growth factor (VEGF) or cytotoxic chemotherapy can boost immunogenicity and has the potential to upregulate ICI efficacy. Methods: A comprehensive electronic literature search was conducted up to April 2025 to identify randomized controlled trials comparing cytotoxic chemotherapy plus bevacizumab with or without ICI. The primary outcome was progression-free survival (PFS), and secondary outcomes were overall survival (OS), objective response rate (ORR), and severe adverse events (AEs: grade 3 or more). A meta-analysis was performed using random-effects models to calculate hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (CIs). Results: Four studies involving 986 patients (With-ICI group, n = 651; Without-ICI group, n = 335) were included. The meta-analysis demonstrated a significant improvement in PFS in the With-ICI group compared with the Without-ICI group, with an HR of 0.82 (95% CI: 0.70–0.96, p = 0.01) without statistical heterogeneity. No significant improvements were observed between the With- and Without-ICI groups in OS and ORR meta-analyses, but the With-ICI group had a favorable trend in OS. A significant increase in serious AEs was not observed in the With-ICI group. Conclusions: This meta-analysis suggests a potential benefit of adding ICIs to chemotherapy plus bevacizumab in pMMR mCRC; however, the evidence remains preliminary and hypothesis-generating, warranting further investigation in biomarker-driven trials and clarification of long-term outcomes. Full article

T-cells constitute an essential component of the adaptive immune response, mount a protective response against foreign pathogens and are important regulators of anti-tumor immunotherapy. In this context, the activation of T-cells and chimeric antigen receptor (CAR)-expressing T-cells is orchestrated by various signaling pathways, involving the initiation of a protein tyrosine phosphorylation cascade. For T-cells, this involves initiation of the phosphorylation cascade via src-related protein-tyrosine kinase p56^lck, which we show to associate with the co-receptors CD4 and CD8 for the induction of a phosphorylation cascade needed for the activation of T-cells. Likewise, p56^lck phosphorylation of the antigen receptor immunoreceptor tyrosine-based activation motifs (ITAMs) and key CD28 tyrosine motifs ensures the functionality and the survival of CARs, while their phospho-targets are also inhibited by PD-1, a key component of the immune checkpoint blockade. This review covers historic and current elements of our knowledge of CD4/CD8–p56^lck-induced activation events and their importance to the development of CAR T-cell immunotherapies. Full article

Early diagnosis of lung cancer is crucial for improving patient prognosis. In this study, we developed a diagnostic model for lung cancer based on serum proteomic data from the GSE168198 dataset using four machine learning algorithms (nnet, glmnet, svm, and XGBoost). The model’s performance was validated on datasets that included normal controls, disease controls, and lung cancer data containing both. Furthermore, the model’s diagnostic capability was further validated on an independent external dataset. Our analysis identified SLC16A4 as a key protein in the model, which was significantly downregulated in lung cancer serum samples compared to normal controls. The expression of SLC16A4 was closely associated with clinical pathological features such as gender, tumor stage, lymph node metastasis, and smoking history. Functional assays revealed that overexpression of SLC16A4 significantly inhibited lung cancer cell proliferation and induced cellular senescence, suggesting its potential role in lung cancer development. Additionally, correlation analyses showed that SLC16A4 expression was linked to immune cell infiltration and the expression of immune checkpoint genes, indicating its potential involvement in immune escape mechanisms. Based on multi-omics data from the TCGA database, we further discovered that the low expression of SLC16A4 in lung cancer may be regulated by DNA copy number variations and DNA methylation. In conclusion, this study not only established an efficient diagnostic model for lung cancer but also identified SLC16A4 as a promising biomarker with potential applications in early diagnosis and immunotherapy. Full article

Immune checkpoint inhibitors (ICIs) are approved in at least one line of therapy for most patients with advanced non-small cell lung cancer (NSCLC) without EGFR/ALK alterations and have improved survival for a subset of patients. Adjuvant, neoadjuvant, and perioperative therapy for resectable NSCLC carries the hope of more broadly increased cure rates for patients with resectable lung cancers. This review summarizes the current state of multimodality management, including ICIs, for resectable NSCLC. A literature search of PubMed and Scopus identified phase II and III clinical trials including ICIs in patients with resectable NSCLC. No level 1 evidence guides the clinician in choosing between the available neoadjuvant and perioperative approaches. Full article

Hepatocellular carcinoma (HCC) remains a therapeutic challenge due to metabolic plasticity and drug resistance. Oncolytic viruses (OVs), such as thymidine kinase-deleted vaccinia virus (oncoVV), selectively lyse tumors while stimulating antitumor immunity, however, their metabolic interplay with cancer cells is poorly understood. Here, we engineered an oncoVV-expressing Aphrocallistes vastus lectin (oncoVV-AVL) and uncovered its unique ability to exploit the ACSS2/TFEB axis, driving metabolic competition in HCC. In vitro, oncoVV-AVL triggered cell autophagy and lipid accumulation (3.4–5.7-fold upregulation of FASN and ACC1) while suppressing glucose uptake (41–63% higher extracellular glucose and 33–34% reduced lactate). Mechanistically, oncoVV-AVL upregulated acetyl-CoA synthetase 2 (ACSS2), promoting its nuclear translocation and interaction with transcription factor EB (TFEB) to concurrently activate lipogenesis and autophagic flux. The pharmacological inhibition of ACSS2 abolished these effects, confirming its central role. In vivo, oncoVV-AVL suppressed tumor growth while inducing lipid deposition (2-fold triglyceride increase), systemic hypoglycemia (42% glucose reduction), and autophagy activation (elevated LC3B-II/I ratios). This study establishes ACSS2 as a metabolic checkpoint in OV therapy, providing a rationale for combining oncolytic virotherapy with metabolic modulators in HCC. Full article

Background/Objectives: Bladder cancer is a malignant disease that causes more than 199,922 deaths a year globally, in which ~75% of all newly diagnosed cases are non-muscle-invasive bladder cancer (NMIBC). Despite a number of treatments available, most NMIBC patients with high-grade tumors eventually recur. To add a novel therapy to complement the deficits of the current treatments, this study assesses the antitumor activity and mechanisms of action of intravesical xenogeneic urothelial cell (XUC) treatment as monotherapy and in combination with either chemotherapy or immune checkpoint inhibition (ICI). Methods: The orthotopic NMIBC graft tumor-bearing mice were randomly assigned into different treatment groups, receiving either intravesical XUCs, gemcitabine, anti-programmed death-ligand 1 (PD-L1) antibodies alone or in combination with gemcitabine or anti-PD-1 antibodies. The tumor responses, survival, and immune reactions were analyzed. Results: Intravesical XUC treatment exhibited significantly more antitumor activity to delay tumor progression than the control group and a similar effect to chemotherapy and ICI. In addition, there were significantly higher effects in the combined groups than single treatments. Immune tumor microenvironment and immune cell proliferation, cytotoxicity, and cytokine secretion were also activated by XUC treatment. Moreover, the combined groups have the highest effects. Conclusions: In vivo and ex vivo studies showed increased antitumor efficacy and immune responses by intravesical XUC treatment in single and combined treatments, suggesting a potential utility of this xenogeneic cell immunotherapeutic agent. Intravesical XUC treatment has the potential to address the substantial unmet need in NMIBC therapy as a bladder-sparing treatment option for NMIBC. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) has recently become the leading cause of chronic liver disease and can progress to hepatocellular carcinoma (HCC) through multiple pathogenic mechanisms. Protease-activated receptor 2 (PAR2) is a G-protein-coupled receptor activated by proteases such as trypsin, tryptase or coagulation factors VII and Xa. Recent studies have shown that PAR2 expression is increased in the liver of patients with MASLD or liver fibrosis. Its activation is linked to metabolic dysfunction through several pathways, including SREBP1c activation, AMPK inhibition and Akt-induced insulin resistance. Inhibition of PAR2 has been effective in reducing MASLD progression in different animal models. Notably, PAR2 blockade has also been effective in more advanced stages of the disease by dampening chronic inflammation and fibrogenesis through the inhibition of hepatic stellate cell activation and of TGF-β and SerpinB3 production. PAR2 also plays a role in cancer development, promoting tumour proliferation, angiogenesis and expression of immune checkpoint inhibitors (like PD-L1, CD47 and CD24). Due to its multifaceted involvement in liver disease, PAR2 is emerging as a key therapeutic target in this clinical context. This review aims to summarise current knowledge on PAR2′s role in MASLD and its potential as a therapeutic target. Full article

The indications for immune checkpoint inhibitor (ICI) use in cancer treatment continue to expand. This is attributable to their proven anticancer activity in addition to their tolerability and favorable toxicity profile as compared to conventional chemotherapeutic agents. ICIs work by blocking the inhibitory signals between tumor cells and T-cells, thereby enhancing the T-cell cytotoxic activity to inhibit tumor growth. Because of their immune-stimulating effect, ICIs are linked to adverse renal outcomes in both native and transplanted kidneys. The risk of kidney allograft rejection in the setting of ICI use has been reported to be around 40%, leading to an increased risk of graft loss. In this report, we review the literature examining outcomes in kidney transplant recipients receiving ICIs for various oncologic indications. Full article

The transcriptional co-factor cell-cycle-related and expression-elevated protein in tumors (CREPT) has emerged as a critical driver of the cell cycle and a significant contributor to tumorigenesis. The aberrant expression or upregulation of CREPT boosts multiple signaling pathways, including Wnt/β-catenin, STAT3 and NF-κB/TNFR2, which are frequently dysregulated in various cancers and are associated with poor overall survival. In preclinical studies, CREPT knockdown via shRNA has demonstrated sustained tumor growth regression. Recent researches have uncovered additional functions of CREPT, including roles in metabolic regulation, tissue repair, and microenvironmental remodeling, further establishing it as a pleiotropic transcriptional regulator. Currently, there is no therapeutic agent that directly inhibits CREPT expression in clinic. However, miRNAs and other methods have been used to target CREPT, which have yielded useful results in inhibiting tumor growth. In this review, we discuss the role of CREPT in the hallmarks of cancer and propose that targeting CREPT will reverse tumor growth and may improve the immune checkpoint inhibitors in combination in CREPT-driven cancers. Full article

Thyroid cancer, the most frequently occurring endocrine neoplasm, comprises a heterogeneous group of histological subtypes, spanning from the indolent papillary thyroid carcinoma (PTC) to the rapidly progressive and lethal anaplastic thyroid carcinoma (ATC). Although conventional therapies, such as surgery and radioactive iodine (RAI), are effective for differentiated thyroid cancers, treatment resistance and poor prognosis remain major challenges in advanced and undifferentiated forms. In current times, growing attention has been directed toward the potential of Natural Killer (NK) cells as a promising immunotherapeutic avenue. These innate immune cells are capable of direct cytotoxicity against tumor cells, but their efficiency is frequently compromised by the immunosuppressive tumor microenvironment (TME), which inhibits NK cell activation, infiltration, and persistence. This review explores the dynamic interaction between NK cells and the TME in thyroid cancer, detailing key mechanisms of immune evasion, including the impact of suppressive cytokines, altered chemokine landscapes, and inhibitory ligand expression. We further discuss latest advancements in NK cell-based immunotherapies, including strategies for ex vivo expansion, genetic modification, and combinatorial approaches with checkpoint inhibitors or cytokines. Additionally, emerging modalities, such as NK cell-derived extracellular vesicles, are addressed. By combining mechanistic insights with advancing therapeutic techniques, this review provides a comprehensive perspective on NK cell-based interventions and their future potential in improving outcomes for patients with thyroid cancer. Full article

The 90 kDa heat shock proteins (Hsp90) are molecular chaperones that regulate the stability and maturation of numerous client proteins implicated in the regulation of cancer hallmarks. Despite the potential of pan-Hsp90 inhibitors as anticancer therapeutics, their clinical development has been hindered by on-target toxicities, particularly ocular and cardiotoxic effects, as well as the induction of pro-survival, compensatory heat shock responses. Together, these and other complications have prompted the development of isoform-selective Hsp90 inhibitors. In this review, we discuss the molecular bases for Hsp90 function and inhibition and emphasize recent advances in isoform-selective targeting. Importantly, we highlight how Hsp90 inhibition can sensitize tumors to cancer immunotherapy by enhancing antigen presentation, reducing immune checkpoint expression, remodeling the tumor microenvironment, and promoting innate immune activation. Special focus is given to Hsp90β-selective inhibitors, which modulate immunoregulatory pathways without eliciting the deleterious effects observed with pan-inhibition. Preclinical and early clinical data support the integration of Hsp90 inhibitors with immune checkpoint blockade and other immunotherapeutic modalities to overcome resistance mechanisms in immunologically cold tumors. Therefore, the continued development of isoform-selective Hsp90 inhibitors offers a promising avenue to potentiate cancer immunotherapy with improved efficacy. Full article

Background/Objectives: Lung cancer is a highly diverse disease, and reliable preclinical models that accurately reflect tumor characteristics are essential for studying lung cancer biology and testing new therapies. This study aimed to establish patient-derived tumor organoids (PDTOs) using small biopsy samples and surgical specimens to create a model system that preserves the genetic and histological features of the original tumors. Methods: PDTOs were generated from 163 lung cancer specimens, including 109 samples obtained using endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) or bronchoscopy, 52 surgical specimens, and 2 pleural fluid samples. The organoid establishment rate beyond passage three was assessed, and histological subtypes and genetic profiles were analyzed using immunohistochemical staining and targeted exome sequencing. Results: The overall PDTO establishment rate was 34.4% (56/163), and 44.6% (25/56) of these organoids retained the histological and genetic features of the parental tumors. Genetic analysis identified key mutations, including KRAS G12C, EGFR L858R, MET exon 14 skipping mutation, and ROS1 fusion. PDTOs successfully formed tumors in mice while maintaining the genetic characteristics of the original tumors. Co-culture of PDTOs with cancer-associated fibroblasts (CAFs) resulted in increased resistance to paclitaxel. In the co-culture model of PDTOs with immune cells, dose-dependent growth inhibition of PDTOs was observed in response to immune checkpoint inhibitors. Conclusions: PDTOs established from small biopsy and surgical specimens serve as a valuable model for studying lung cancer biology, tumor microenvironment interactions, and drug response. This model has the potential to improve personalized treatment strategies. Full article

Marine-derived compounds represent a rich source of structurally diverse molecules with therapeutic potential for cancer, renal disorders, metabolic-associated fatty liver disease (MAFLD), and atherosclerosis. This review systematically evaluates recent advances, highlighting compounds such as Microcolin H, Benzosceptrin C, S14, HN-001, Equisetin, glycosides (e.g., cucumarioside A₂-2), ilimaquinone, and Aplidin (plitidepsin). Key mechanisms include autophagy modulation, immune checkpoint inhibition, anti-inflammatory effects, and mitochondrial homeostasis. Novel findings reveal glycosides’ dual role in cytotoxicity and immunomodulation, ilimaquinone’s induction of the DNA damage response, and Aplidin’s disruption of protein synthesis via eEF1A2 binding. Pharmacokinetic challenges and structure–activity relationships are critically analyzed, emphasizing nanodelivery systems and synthetic analog development. This review bridges mechanistic insights with translational potential, offering a cohesive framework for future drug development. Full article

This manuscript assesses the critical role of exosomal PD-L1 (ExoPD-L1) in immune suppression, tumor progression, and resistance to therapy. ExoPD-L1 has been identified as a key mediator of tumor immune evasion, contributing to systemic immunosuppression beyond the tumor microenvironment (TME) due to its capacity to travel to distant anatomical sites. In this context, the review aims to elaborate on the mechanisms by which exosomal PD-L1 interacts with T cell receptors and modulates both the tumor microenvironment and immune responses, impacting patient outcomes. We further explore emerging therapeutic strategies that target ExoPD-L1 to enhance the effectiveness of immunotherapy. Blocking ExoPD-L1 offers a novel approach to counteracting immune escape in cancer. Promising strategies include inhibiting exosome biogenesis with GW4869 or Rab inhibitors, neutralizing ExoPD-L1 with targeted antibodies, and silencing PD-L1 expression through RNA interference (RNAi) or CRISPR-based methods. While each approach presents certain limitations, their integration into combination therapies holds significant potential to improve the efficacy of immune checkpoint inhibitors. Future research should focus on optimizing these strategies for clinical application, with particular attention to improving delivery specificity and minimizing off-target effects. Full article

Background: Esophageal squamous cell carcinoma (ESCC) is a fatal malignant tumor. Several studies have demonstrated that immune checkpoint inhibitors can provide clinical benefits to patients with ESCC. However, the single-agent efficacy of these agents remains limited. Although combination therapies (e.g., radiotherapy, chemotherapy) can help to overcome immunotherapy resistance in ESCC, their severe side effects limit clinical application. This study aimed to explore new resistance mechanisms to immunotherapy in ESCC and identify novel molecular targets to overcome immunotherapy resistance. Methods: We employed immunohistochemistry staining to examine the p-FGFR1^Y654 in tumor samples obtained from 103 patients with ESCC, in addition to evaluating CD8+ T cell infiltration. In vitro expression, western blotting, CCK-8, 5-bromo-2′-deoxyuridine incorporation assays, and migration assays were used to confirm the impact of AZD4547 on p-FGFR1^Y654 expression and the proliferation and migration in ESCC cell lines. Through RNA sequencing analysis, databases such as the Cancer Genome Atlas (TCGA) and Gene Set Cancer Analysis (GSCA), and the reconstruction of transgenic mice using the humanized immune system, we validated the correlation between the expression of p-FGFR1^Y654 and CD8+ T cell infiltration. We also explored how p-FGFR1^Y654 recruits myeloid-derived suppressor cells (MDSCs) through the CXCL8–CXCR2 axis to suppress the therapeutic efficacy of immunotherapy in ESCC. Finally, the tumor-suppressive effects of AZD4547 combined with immunotherapy were confirmed in vivo in tumor-bearing mice with a humanized immune system. Results: We found that the inhibition of p-FGFR1^Y654 expression in ESCC can enhance CD8+ T cell infiltration by suppressing the CXCL8-–XCR2 recruitment of MDSCs. AZD4547, combined with immunotherapy, further promotes immunotherapeutic efficacy in ESCC. Conclusions: In conclusion, our study presents a promising model for combination therapy in ESCC immunotherapy. Full article